Substituted azetidin-2-ones for treatment of atherosclerosis

ABSTRACT

Compounds of formula (I) in which R 1  and R 2 , which may be the same or different, is each selected from hydrogen, halogen or C.sub.(1-8) alkyl; R 3  is aryl or aryl C.sub.(1-4) alkyl which may be optionally substituted; X is a linker group; Y is an optionally substituted aryl group; and n is 0, 1 or 2; are inhibitors of the enzyme Lp-PLA 2  and thereof of use in treating atherosclerosis.

This application is a 371 application of International ApplicationPCT/EP95/05130, filed on Dec. 20, 1995.

The present invention relates to certain novel monocyclic β-lactamcompounds, processes for their preparation, intermediates useful intheir preparation, pharmaceutical compositions containing them and theiruse in therapy, in particular in the treatment of artherosclerosis.

Lipoprotein Associated Phospholipase A₂ (Lp-PLA₂). The sequence of theenzyme, the isolation and purification thereof, isolated nucleic acidsencoding the enzyme, recombinant host cells transformed with DNAencoding the enzyme are described in patent application WO 95/00649(SmithKline Beecham plc). Suggested therapeutic uses for inhibitors ofthe enzyme included artherosclerosis, diabetes, rheumatoid arthritis,stroke, myocardial infarction, reperfusion injury and acute and chronicinflammation. A later patent application (WO 95/09921, Icos Corporation)and a related publication in Nature (Tjoelker et al, vol 374, Apr. 6,1995, 549) describe the same enzyme, although calling it by the name`Platelet Activating Factor Acetyl Hydrolase` (PAF acetyl hydrolase) andsuggest that it may have potential as a therapeutic protein forregulating pathological inflammatory events.

Lp-PLA₂ is responsible for the conversion of phosphatidylcholine tolysophosphatidylcholine, during the conversion of low densitylipoprotein (LDL) to its oxidised form. The enzyme is known to hydrolysethe sn-2 ester of oxidised phosphatidylcholine to givelysophosphatidylcholine and an oxidatively modified fatty acid. Bothproducts of Lp-PLA₂ action are biologically active withlysophosphatidylcholine, a component of oxidised LDL, known to be apotent chemoattractant for circulating monocytes. As such,lysophosphatidylcholine is thought play a significant role inatherosclerosis by being responsible for the accumulation of cellsloaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA₂enzyme would therefore be expected to stop the build up of thesemacrophage enriched lesions (by inhibition of the formation oflysophosphatidylcholine and oxidised free fatty acids) and so be usefulin the treatment of atherosclerosis.

The increased lysophosphatidylcholine content of oxidatively modifiedLDL is also thought to be responsible for the endothelial dysfunctionobserved in patients with atherosclerosis. Inhibitors of Lp-PLA₂ couldtherefore prove beneficial in the treatment of this phenomenon. ALp-PLA₂ inhibitor could also find utility in other disease states thatexhibit endothelial dysfunction including diabetes, hypertension, anginapectoris and after ischaemia and reperfusion.

Lp-PLA₂ inhibitors may also have a general application in any disorderthat involves activated monocytes, macrophages or lymphocytes, as all ofthese cell types express Lp-PLA. Examples of such disorders includepsoriasis.

Lp-PLA₂ inhibitors may also have a general application in any disorderthat involves lipid peroxidation in conjunction with Lp-PLA₂ activity toproduce the two injurious products, lysophosphatidylcholine andoxidatively modified fatty acids. Such conditions include theaforementioned conditions atherosclerosis, diabetes, rheumatoidarthritis, stroke, inflammatory conditions of the brain such asAlzheimer's Disease, myocardial infarction, reperfusion injury, sepsisand acute and chronic inflammation. Further such conditions includevarious neuropsychiatric disorders such as schizophrenia (seePsychopharmacology Bulletin, 31, 159-165, 1995).

We have now identified a series of compounds which have been found toact as inhibitors of Lp-PLA₂.

Accordingly, the present invention provides a compound of formula (I):##STR2## in which: R¹ and R², which may be the same or different, iseach selected from hydrogen, halogen or optionally substitutedC.sub.(1-8) alkyl;

R³ is aryl or aryl C.sub.(1-4) alkyl which may be optionallysubstituted;

X is a linker group;

Y is an optionally substituted aryl group; and

n is 0, 1 or 2.

Compounds of formula (I) are inhibitors of Lp-PLA₂ and as such areexpected to be of use in treating atherosclerosis and the other diseaseconditions noted above.

Representative examples of R¹ and R² include hydrogen, bromo, methyl andethyl, optionally substituted with hyroxyl. Suitably, R¹ and R² is eachhydrogen or one of R¹ and R² is hydrogen and the other of R¹ and R² ismethyl (to give a trans-methyl). Preferably, R¹ and R² is each hydrogen.

Within R³, representative examples of the aryl group include phenyl andnaphthyl. Suitably, R³ is aryl C(.sub.(1-3) alkyl. Suitable examples ofR³ include phenyl, benzyl, 2-phenylethyl and 3-phenylpropyl in each ofwhich the phenyl ring may be optionally substituted by up to threesubstituents. It will be appreciated that an optional substituent may belocated in the aryl portion and/or the alkyl portion (if present).Preferably, R³ is optionally substituted benzyl, preferably substitutedat the 4-position. Suitable substituents for a phenyl or naphthyl ringin R³ include halo, hydroxy, C.sub.(1-6) alkyl, C.sub.(1-6) alkoxy,carboxy, C.sub.(1-6) alkoxy-carbonyl, C.sub.(2-6) alkenyloxycarbonyl,carboxy C.sub.(1-6) alkyl and C.sub.(1-6) alkoxy-carbonyl C.sub.(1-6)alkyl. More preferably, R³ is 4-carboxybenzyl or a correspondingC.sub.(1-6) alkyl or C.sub.(2-6) alkenyl ester thereof.

Preferably, n is 1 or 2 more preferably 1.

Preferably, S(O)_(n) R³ is optionally substituted benzylsulphinyl, morepreferably 4-carboxybenzylsulphinyl or a corresponding C.sub.(1-6) alkylor C.sub.(2-6) alkenyl ester thereof.

Suitably X is a direct bond; a group X'(CH₂)_(m) in which X' is CO,CONR⁵, COO, CONR⁵ CO, or CONHO in which R⁵ is hydrogen or C.sub.(1-6)alkyl and m is 0 or an integer from 1 to 12; or a C.sub.(1-12) alkylenechain optionally interupted by X'. Representative examples of X includeCO(CH₂)_(m), CONH(CH₂)_(m), COO(CH₂)_(m), CONHCO(CH₂)_(m),CONHO(CH₂)_(m) and C.sub.(1-12) alkylene. Preferably, X' is CO or CONR⁵,more preferably CONH. Preferably, m is 1, 2, 5, 6, 7 or 9, preferably 6.Preferably, X is CONH(CH₂)₆.

Suitably, Y is a benzene ring, optionally substituted by up to threefurther substituents. Suitable substituents include halo, hydroxy,C.sub.(1-8) alkyl and C.sub.(1-8) alkoxy. Preferably, Y is phenyloptionally substituted by halo, more preferably 4-chloro or4-fluoro-phenyl, most preferably, 4-fluoro-phenyl.

It will be readily appreciated by the skilled person that C-4 of theβ-lactam ring is a chiral centre which will give rise to the presence ofstereoisomers. The present invention encompasses all such stereoisomers.

It will be further readily appreciated by the skilled person that, incompounds of formula (I) in which n is 1, that is sulphoxide compounds,the presence of the SO moiety will introduce an additional chiral centreinto the molecule and therefore give rise to the existence of extrastereoisomers. The present invention encompasses all such stereoisomers.

In preferred compounds of formula (I), the relative configurations atC-4 and the SO moiety are R,S and S,R and in the most preferredcompounds the absolute configurations at C-4 and the SO moiety are R andS respectively.

When used herein, the term `alkyl` and similar terms such as `alkoxy`includes all straight chain and branched isomers. Representativeexamples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

Suitable substituents for an alkyl group include, for example, halogen,cyano, azido, nitro, carboxy, (C₁₋₆)alkoxycarbonyl, carbamoyl, mono- ordi-(C₁₋₆)alkylcarbamoyl, sulpho, sulphamoyl, mono- ordi-(C₁₋₆)alkylsulphamoyl, amino, mono- or di-(C₁₋₆)alkylamino,acylamino, ureido, (C₁₋₆)alkoxycarbonylamino,2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy,(C₁₋₆)alkoxy, acyloxy, oxo, acyl, 2-thienoyl, (C₁₋₆)alkylthio,(C₁₋₆)alkylsulphinyl, (C₁₋₆)alkylsulphonyl, hydroxyimino,(C₁₋₆)alkoxyimino, hydrazino, hydrazono, benzohydroximoyl, guanaidino,amindino and iminoalkylamino.

When used herein, the term `aryl` includes, unless otherwise defined,phenyl or naphthyl optionally substituted with up to five, preferably upto three substituents.

Suitable substituents for an aryl group include, for example, halogen,cyano, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)alkoxy, halo(C₁₋₆)alkyl,hydroxy, amino, mono- or di-(C₁₋₆)alkylamino, acylamino, nitro, carboxy,(C₁₋₆)alkoxycarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₁₋₆)alkoxycarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenoxycarbonyl(C₁₋₆)alkyl,(C₁₋₆)alkylcarbonyloxy, carboxy(C₁₋₆)alkoxy,(C₁₋₆)alkoxycarbonyl(C₁₋₆)alkoxy, (C₂₋₆)alkenoxycarbonyl(C₁₋₆)alkoxy,(C₁₋₆)alkylcarbonyloxy, (C₁₋₆)alkylthio, (C₁₋₆)alkylsulphinyl,(C₁₋₆)alkylsulphonyl, sulphamoyl, mono- and di-(C₁₋₆)-alkylsulphamoyl,carbamoyl, mono- and di-(C₁₋₆)alkylcarbamoyl, and heterocyclyl.

When used herein, the terms `halogen` and `halo` include fluorine,chlorine, bromine and iodine and fluoro, chloro, bromo and iodo,respectively.

Preferred compounds of formula (I) include:

(4R,SS/4S,SR)-N-(6-phenylhexyl)-(4-(4-methoxyphenyl)sulfinyl)-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR)-N-(6-phenylhexyl)-(4-(3,4-dimethoxyphenylsulfinyl)-2-oxoazetidin-1-yl)acetamide;

(4R,SR/4S,SS)N-(6-phenylhexyl)-(4-(3,4-dimethoxyphenylsulfinyl)-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR)-4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;

(4R,SS)-4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;

(4R,SS/4S,SR)-4-(3,4-dimethoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;

(4R,SS/4S,SR)-4-(3-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;

(4R,SS/4S,SR)-4-(4-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;

(R,S/S,R)-N-[6-(4-chlororophenyl)hexyl]-4-(4-methylphenyl)sulfinyl-2-oxo-azetidinyl-1-ylacetamide;

(R,S/S,R)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide;

(+)-(R,S orS,R)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide;

(-)-(R,R orS,S)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide;

(R,S/S,R)-N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxyphenylsulfinyl)-2-oxoazetidin-1-ylacetamide;

N-(6-{4-Fluorophenyl}hexyl)-4-(4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl(acetamide(Diastereoisomer 2);

N-(6-{4-Fluorophenyl}hexyl)-4-(4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2);

N-(6-{4-Fluorophenyl}hexyl)-4-(4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2);

N-(6-{4-Fluorophenyl}hexyl)-4-(4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2);

N-[6-(4-Fluorophenyl)hexyl]-[4-(4-ethyloxycarbonylbenzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide(Diastereoisomer2);N-(6-[4-Fluorophenyl]hex-1-yl)-4-carboxybenzylthio)-2-oxoazetidin-1-ylacetamide;

N-[6-(4-Fluorophenyl)hexyl]-[4-(4-methyloxycarbonylbenzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide(Diastereoisomer 2);

N-(6-{4-Chlorophenyl}hexyl)-4-(4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2);

N-(6-{4-Chlorophenyl}hexyl)-4-(4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2);

N-(6-{4-Chlorophenyl}hexyl)-4-(4-ethyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2);

N-[6-(4-Fluorophenyl)hexyl]-[4-(4-allyloxycarbonylmethyl)benzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide(Diastereomer 2);

N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(carboxymethyl)benzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide(Diastereomer 2);

(4R,SS/4S,SR) 4-(Benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one;

(4R,SS/4S,SR) 4-(Benzylsulphinyl)-1-(9-phenyl-2-oxononyl)azetidin-2-one;

(4R,SS/4S,SR)N-(6-phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR) N-benzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR)N-(9-Phenylnonyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR)N-[6-(3,5-Di-tert-butyl-4-hydroxyphenyl)hexyl]-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

(4R,SR/4S,SS)N-6-(4-methoxyphenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR)N-6-(4-methoxyphenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR)N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

(4R,SS)N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

4R,SS/4S,SR)N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR)N-(6-(3-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR)N-(6-Phenylhexyl)-(4-(4-ethoxycarbonyl)benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;

N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide;

(4R,SS/4S,SR) 4-Benzylsulphinyl-1-(2-phenethyl)azetidin-2-one;

(3S,4R,SR)-N-(6-phenylhexyl)-4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-ylacetamide;

(3S,4R,SR)-N-(6-phenylhexyl)-4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-ylacetamide;

N-(6-[4-chlorophenyl]hex-1-yl)-(4-carboxylbenzylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereoisomer 2);

N-(6-[4-chlorophenyl]hex-1-yl)-(4-methoxycarbonylbenzylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereoisomer 2);

N-(6-[4-chlorophenyl]hex-1-yl)-(4-allyloxycarbonyl-benzylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereoisomer 2).

Since the compounds of the present invention, in particular compounds offormula (I), are intended for use in pharmaceutical compositions, itwill be understood that they are each provided in substantially pureform, for example at least 50% pure, more suitably at least 75% pure andpreferably at least 95% pure (% are on a wt/wt basis). Impurepreparations of the compounds of formula (I) may be used for preparingthe more pure forms used in the pharmaceutical compositions. Althoughthe purity of intermediate compounds of the present invention is lesscritical, it will be readily understood that the substantially pure formis preferred as for the compounds of formula (I). Preferably, wheneverpossible, the compounds of the present invention are obtained incrystalline form.

When some of the compounds of this invention are allowed to crystalliseor are recrystallised from organic solvents, solvent of crystallizationmay be present in the crystalline product. This invention includeswithin its scope such solvates. Similarly, some of the compounds of thisinvention may be crystallised or recrystallised from solvents containingwater. In such cases water of hydration may be formed. This inventionincludes within its scope stoichiometric hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation. In addition, different crystallisationconditions may lead to the formation of different polymorphic forms ofcrystalline products. This invention includes within its scope allpolymorphic forms of the compounds of formula (I).

Compounds of the present invention are inhibitors of the enzymelipoprotein associated phospholipase A₂ (Lp-PLA₂) and as such areexpected to be of use in therapy, in particular in the treatment ofatherosclerosis. In a further aspect therefore the present inventionprovides a compound of formula (I) for use in therapy. The compounds offormula (I) are inhibitors of lysophosphatidylcholine production byLp-LA₂ and may therefore also have a general application in any disorderthat involves endothelial dysfunction, for example atherosclerosis,diabetes, hypertension, angina pectoris and after ischaemia andreperfusion. In addition, compounds of formula (I) may have a generalapplication in any disorder that involves lipid peroxidation inconjunction with enzyme activity, for example in addition to conditionssuch as atherosclerosis and diabetes, other conditions such asrheumatoid arthritis, stroke, inflammatory conditions of the brain suchas Alzheimer's Disease, myocardial infarction, reperfusion injury,sepsis, and acute and chronic inflammation. Further such conditionsinclude various neuropsychiatric disorders such as schizophrenia (seePsychopharmacology Bulletin, 31, 159-165, 1995).

Further applications include any disorder that involves activatedmonocytes, macrophages or lymphocytes, as all of these cell typesexpress Lp-PLA₂. Examples of such disorders include psoriasis.

Accordingly, in a further aspect, the present invention provides for amethod of treating a disease state associated with activity of theenzyme Lp-PLA₂ which method involves treating a patient in need thereofwith a therapeutically effective amount of an inhibitor of the enzyme.The disease state may be associated with the increased involvement ofmonocytes, macrophages or lymphocytes; with the formation oflysophosphatidylcholine and oxidised free fatty acids; with lipidperoxidation in conjunction with Lp PLA2 activity; or with endothelialdysfunction.

Compounds of the present invention may also be of use in treating theabove mentioned disease states in combination with anti-hyperlipidaemicor anti-atherosclerotic or anti-diabetic or anti-anginal oranti-inflammatory or anti-hypertension agents. Examples of the aboveinclude cholesterol synthesis inhibitors such as stains, anti-oxidantssuch as probucol, insulin sensitisers, calcium channel antagonists, andanti-inflammatory drugs such as NSAIDs.

In therapeutic use, the compounds of the present invention are usuallyadministered in a standard pharmaceutical composition. The presentinvention therefore provides, in a further aspect, a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier.

Suitable pharmaceutical compositions include those which are adapted fororal or parenteral administration or as a suppository.

The compounds of formula (I) which are active when given orally can beformulated as liquids, for example syrups, suspensions or emulsions,tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s) for example, ethanol, glycerine, non-aqueous solvent, forexample polyethylene glycol, oils, or water with a suspending agent,preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound of formula (I) in a sterile aqueous carrier or parenterallyacceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone,lecithin, arachis oil or sesame oil. Alternatively, the solution can belyophilised and then reconstituted with a suitable solvent just prior toadministration.

A typical suppository formulation comprises a compound of formula (I)which is active when administered in this way, with a binding and/orlubricating agent such as polymeric glycols, gelatins or cocoa butter orother low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet orcapsule.

Each dosage unit for oral administration contains preferably from 1 to500 mg (and for parenteral administration contains preferably from 0.1to 25 mg) of a compound of the formula (I).

The daily dosage regimen for an adult patient may be, for example, anoral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500mg, or an intravenous, subcutaneous, or intramuscular dose of between0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compoundof the formula (I), the compound being administered 1 to 4 times perday. Suitably the compounds will be administered for a period ofcontinuous therapy, for example for a week or more.

Compounds of formula (I) may be prepared from convenient startingmaterials by adapting synthetic procedures well known in the art. Asuitable process comprises treating an azetidone of formula (II):##STR3## in which: n, R¹, R² and R³ are as hereinbefore defined; with analkylating agent of the formula (III):

    ZCH.sub.2 XY                                               (III)

in which Z is a suitable leaving group such as halogen; and X and Y areas hereinbefore defined; under alkylating conditions.

Suitable alkylating conditions are well known to those skilled in theart and include the use of a suitable base such as sodium hydride orpotassium hydroxide, in a suitable alkylating solvent such astetrahydrofuran (THF), and at a temperature in the range -10 to 0° C.Suitably, alkylation is conveniently effected on compounds of formula(II) in which n is 0.

Compounds of formula (I) in which n is 1 or 2 can be readily preparedfrom compounds of formula (I) in which n is 0 by treatment thereof witha suitable oxidising agent such as m-chloroperbenzoic acid. Use ofchiral oxidising agents such as (+)- or (-)-1,1'-bi-2-naphthol/titaniumisopropoxide (N Komatsu et al, J Org Chem, 1993, 58, 7624-7626) can givediastereoisomeric selectivity, if not chirally pure compounds.

Compounds of formula (II) in which n is 0 may be obtained by treating4-acetoxyazetidinone, 4-benzoyloxyazetidinone or4-phenylsulfonylazetidinone with a thiol R³ SH in the presence of a basesuch as sodium ethoxide, in a suitable solvent such as ethanol at atemperature in the range 0 to 5° C. When this displacement is conductedin the presence of a chiral base, such as chinchonidine or cinchonine,enantiomercially enriched compounds (II) can be obtained (Shibaski etal, JCS Chem. Commum. 1883, 1324).

Compounds of formula (III) may be readily prepared by adapting knownsynthetic procedures, according to the specific value of X. A convenientstarting material is an appropriately substituted aryl compound whichmay then be elaborated to introduce the side chain ZCH_(x) X-.

Compounds of formula (I) in which X denotes a group CONR⁵ (CH₂)_(m)(amide) or CONHO(CH₂)_(m) (hydroxamate) may be conveniently prepared bytreating an acid of the formula (IV): ##STR4## in which: n, R¹, R² andR³ are as hereinbefore defined; with an amine of the formula (V):

    NHR.sup.5 (CH.sub.2).sub.m Y                               (V)

or a hydroxylamine of the formula (VI):

    NH.sub.2 O(CH.sub.2).sub.m Y                               (VI)

in which R⁵, Y and m are as hereinbefore defined, under suitable amideor hydroxamate bond forming conditions (respectively).

Suitable such conditions are well known to those skilled in the art andinclude the use of an activating agent such as ethyl chloroformate ordicyclohexylcarbodiimide (DCC), in a suitable solvent such as chloroformor dimethyl formamide, at a temperature in the range -10 to 20° C.

An acid of formula (IV) may be obtained by treating a compound offormula (II) with a 2-bromoacetate ester, under alkylating conditions,as hereinbefore described; followed by the hydrolysis of the thus formedintermediate ester using standard conditions.

Compounds of formula (I) in which X denotes a group COO(CH₂)_(m) (ester)may be conveniently prepared by transesterifying an ester of formula(VII): ##STR5## in which: p1 R⁶ is (C₁₋₆)alkyl; n, R¹, R² and R³ are ashereinbefore defined; using trans esterifying conditions.

Suitable such conditions are well known in the art and include, forinstance, heating in toluene in the presence of a catalytic amount ofsodium methoxide and an alcohol. Suitably, the compound of formula (VII)is a methyl ester in which R⁶ is methyl.

A compound of formula (VII) may be obtained by treating a compound offormula (II) with an-alkyl 2-bromoacetate, under alkylating conditions,as hereinbefore described.

Compounds of formula (VII) are novel compounds which are useful asintermediates to compounds of formula (I).

Accordingly, in a further aspect, the present invention provides forcompounds of formula (VII) as hereinbefore defined.

The compounds of formula (VII) are also inhibitors of the enzyme Lp-PLA₂and therefore of use in the various diseases hereinbefore described forcompounds of formula (I).

Alternatively, a compound of formula (I) in which X denotes a groupCOO(CH₂)_(m) (ester) may be prepared by treating a compound of formula(IV) with an alcohol Y(CH₂)_(m) OH or an activated derivative thereof,for instance a tosylate.

In addition, compounds of formula (I) in which n is 0 may be prepared bya process which comprises treating a compound of formula (VIII):##STR6## in which R¹, R² and R³ are as hereinbefore defined; with analkylating agent of the formula (IX):

    R.sup.3 Z                                                  (IX)

in which R³ and Z are as hereinbefore defined; under suitable alkylatingconditions, for instance, in a solvent such as acetonitrile, at atemperature in the region 25° C.

Compounds of formula (VIII) may be obtained from the corresponding4-acetylthioazetidinone by treatment with silver nitrate and a base in asuitable solvent such as methanol.

Mixtures of diastereoisomeric compounds of formula (I) may be resolved,if so desired, according to procedures well known in the art. Forinstance sulphoxides (n=1) may be separated by chromatography and/orcrystallisation. Chirally pure compounds may be prepared by chiralchromatography, from chirally pure intermediates or by chiral synthesisusing chiral reagents or catalysis. Suitable chiral intermediates may beobtained by resolution or chiral induction or by using chiral reagents,in particular natural chiral molecules, according to methods well knownto those skilled in the art. For chiral synthesis, a convenient chiralstarting material is a penicillin derivative which has the preferredconfiguration at C-4of the β-lactam ring. This is illustrated in thefollowing scheme: ##STR7## The preparation of the starting material(4-methoxybenzyl-6-bromopenicillinate-1-oxide) is described in J. Chem.Soc., Perkin Trans., 1, 1994, 179-188.

The present invention will not be illustrated by the following examples.In these examples diastereoisomers of sulfoxide compounds are referredto as having R,R/S,S or R,S/S,R configurations. Such configurations wereobtained initially by x-ray analysis of a limited number of compoundsand then extrapolated to the remaining compounds on the basis of their ¹H NMR spectra. Unless otherwise specified, all compounds are racemic.Chiral compounds are described as 4R or S,SR or S where the 4 describesthe centre at the C4 position in the azetidinone and the S describes thesulfoxide centre. Where mixtures of sulfoxides were obtained thespectral data is given for both (50:50 mixtures) or for the major isomer(e.g. 90:10 mixtures). All compounds are characterised by NMR and mostby microanalysis and mass spec.

PREPARATIONS Preparation 1 6-(4-Methoxyphenyl)hexylamine

a. 6-Bromo-1-(4-methoxyphenyl)hexane

A solution of 6-bromohexanoyl chloride (50 g, 0.2 mol) in drydichloromethane (40 ml) was added dropwise over 5 minutes to asuspension of aluminium chloride (31 g, 0.2 mol) in dry dichloromethane(100 ml), keeping the temperature between 20-23° C. The mixture wasstirred for 30 minutes at room temperature to give a yellow solution.Anisole (23 g, 0.2 mol) in dry dichloromethane (30 ml) was added andstirred for 20 hours at room temperature. Triethylsilane (59.9 g, 0.515mol) was added over 10 minutes, maintaining the temperature between 25°C.-35° C. The solution was stirred for 60 minutes at room temperatureand poured onto ice/water (200 g). The organic layer was washed withbrine and water until the pH of the solution was neutral. Drying (MgSO₄)and evaporation under reduced pressure gave a yellow oil which wasdistilled under reduced pressure at 90-110° C./0.5 mbar. Producecontaining fractions were combined and purified by flash chromatographyon silica gel using hexane as eluant to give a colourless oil (18.33 g,33%).

b. N-(4-Methoxybenzyl)-6-hexyl phthalimide

6-Bromo-1-(4-methoxyphenyl)hexane (26.5 g, 0.1 mol) was dissolved in DMF(140 ml), potassium phthalimide (36.2 g, 0.2 mol) was added and themixture stirred at 100° C. for 18 hours. The mixture was evaporated, theresidue taken up in ether and excess potassium phthalimide filtered off.The filtrate was washed with water, dried (MgSO₄) and evaporated to ayellow solid which was recrystallised from ether/petroleum ether to givea pale yellow solid (20.0 g, 61%) mp 63°-65° C.

c. 6-(4-Methoxyphenyl)hexylamine

N-(4-methoxybenzyl)-1-hexyl phthalimide (19.9 g, 60 mmol) was dissolvedin ethanol (300 ml) and hydrazine monohydrate (8.9 g, 0.11 mol) wasadded. The mixture was refluxed for 3 hours, filtered, the residuewashed with ethanol and the filtrate evaporated. The residue was takenup in diethyl ether, filtered and the residue washed well with ether.Evaporation of the filtrate gave a yellow oil which was purified bydistillation to give a clear oil bp 108-110° C., 0.02 mbar.

Preparation 2 6-(3,5-di^(t) butyl-4-hydroxyphenyl)hexylamine

This was prepared from 3,5-di^(t) butyl-4-hydroxy phenol according tothe general procedure of Preparation 1.

Preparation 3 6-(3-chlorophenyl)hexylamine

a. 6-(3-chlorophenyl)hexyn-1-ol

A stirred mixture of 3-chloroiodobenzene (14.3 g, 60 mmol),tetrakis(triphenylphosphine) palladium (2.1 g, 1.8 mmol) and5-hexyn-1-ol (5.9 g, 60 mmol) in triethylamine (120 ml) was stirred at25° C. for 3 h and partitioned between water and ether. The ether layerwas separated and the aqueous extracted with ether. The combined eitherextracts were washed with 1N HCl and dried (Na₂ SO₄). The ether wasevaporated and the residue purified by flash chromatography on silicausing dichloromethane as eluant. Evaporation of the appropriatefractions gave the product as an oil (11.5 g 92%)

b. 1-(Phthalimido)-6-(3-chlorophenyl)hex-1-yne

A solution of 6-(3-chlorophenyl)hexyn-1-ol (11.5 g, 55 mmol),triphenylphosphine (14.5 g, 55 mol) and phthalimide (8.1 g, 55 mol) indry THF (110 ml) was treated with a solution of DEAD (9.6 g, 55 mmol) inTHF (20 ml) over several minutes. After 16 h, volatiles were removed invacuo and the residue treated with ether. The precipitated solid wasremoved, the filtrate evaporated and the residue purified by flashchromatography on silica using dichloromethane as eluant. Evaporation ofthe appropriate fractions gave the product as a solid (16.5 g, 89%)

c. 6-(3-chlorophenyl)hexylamine

A suspension of 1-(phthalimido)-6-(3-chlorophenyl)hex-1-yne (10 g, 30mmol) in methanol (100 ml) was treated with platinum oxide (250 mg) andthe mixture hydrogenated at 50 psi for 72 h. Further quantities ofcatalyst were added at intervals and when the theoretical uptake ofhydrogen was complete, the mixture was filtered and the filtrateevaporated to a brown oil (9.5 g, 96%). This was dissolved in IMS 99(100 ml) and treated with hydrazine hydrate (2.8 g, 56 mmol) underreflux for 16 h. The mixture was cooled to 5° C. and the precipitatedsolid removed by filtration. Evaporation of the filtrate gave an oilwhich was taken up in ether, washed with water, dried (Na₂ SO₄) andevaporated to a brown oil (5.8 g, 98%)

Preparation 4 6-(3,5-dichlorophenyl)hexylamine

This was prepared using the general procedure of Preparation 3 andobtained as an oil.

Preparation 5-4-(4-(Allyloxycarbonyl)benzylthio)azetidin-2-one

a. Allyl 4-(bromomethyl)benzoate

4-(Bromomethyl)benzoic acid (103 g, 0.48 moles) was suspended in thionylchloride (200 ml) and dimethylformamide (1 ml) was added. The mixturewas heated under reflux until clear, evaporated and azeotroped withtoluene (2×150 ml). The resulting oil was dissolved in dichloromethaneand added dropwise to a cooled solution of pyridine (42 ml) and allylalcohol (40 ml) in dichloromethane. The mixture was stirred at roomtemperature for 1 hour, then washed with water, 2M hydrochloric acid,sodium hydrogen carbonate solution and brine. The organic solution wasdried and evaporated to give allyl 4-(bromomethyl)benzoate as a clearoil (98 g, 84% yield). ¹ H NMR δ (CDCl₃) 4.61 (2H, s, CH₂), 4.82 (2H, m,CH₂ O), 5.34 (2H, m, CH₂ CH--), 6.05 (1H, m, CHCH₂), 7.45 (2H, d, Ph-H),8.03 (2H, d, Ph-H).

b. Allyl 4-(acetylthiomethyl)benzoate

Allyl 4-(bromomethyl)benzoate (98 g, 0.4 moles) in dry dimethylformamide(100 ml) was added dropwise to a cooled suspension of potassiumthioacetate (46 g, 0.4 moles) in dry dimethylformamide (200 ml). Thecooling bath was removed and the mixture was stirred overnight. Thereaction was poured into water and extracted with ethyl acetate (×3).The combined extracts were washed with water and brine. The mixture wasdried and evaporated to give allyl 4-(acetylthiomethyl)benzoate as anorange oil (100 g, 100% yield). ¹ H NMR δ (CDCl₃) 2.36 (3H, s, COCH₃),4.13 (2H, s, CH2), 4.82 (2H, m, CH₂ O), 5.32 (2H, m, CH₂ CH--), 6.05(1H, m, CHCH₂), 7.35 (2H, d, Ph-H), 7.98 (2H, d, Ph-H).

c. 4-(4-(Allyloxycarbonyl)benzylthio)azetidin-2-one

Allyl alcohol (27 ml) in dry tetrahydrofuran (50 ml) was added dropwiseto a solution of potassium tert-butoxide (4.93 g, 0.044 moles) in drytetrahydrofuran (100 ml). After stirring for 5 minutes a solution ofallyl 4-(acetylthiomethyl)benzoate (10.1 g, 0.04 moles) in drytetrahydrofuran (100 ml) was added dropwise. After stirring for 15minutes a solution of 4-acetoxyazetidin-2-one (5.16 g, 0.04 moles) wasadded dropwise. The mixture was stirred for 1 hour and evaporated. Theresidue was partitioned between ethyl acetate and water and the aqueouswas extracted with ethyl acetate. The combined extracts were washed withbrine, dried and evaporated. Flash chromatography (silica gel, ethylacetate-petrol) gave 4-(4-Allyloxycarbonylbenzylthio)azetidin-2-one asan oil (9.1 g, 82% yield. ¹ H NMR δ (CDCl₃) 2.84 (1H, dd, H3a), 4.31(1H, dd, H3b), 3.88 (2H, s, S--CH2), 4.68 (1H, dd, H4), 4.78 (2H, m, CH₂O), 5.35 (2H, m, CH₂ CH--), 6.05 (1H, m, CHCH₂), 6.07 (1H, br. singlet,N--H), 7.40 (2H, d, Ph-H), 8.03 (2H, d, Ph-H).

Preparation 6-4-(4-(Allyloxycarbonylmethyl)benzylthio)azetidin-2-one.

a. Allyl 4-(bromomethyl)phenylacetate

Colourless oil, 95% yield. ¹ H NMR δ (CDCl₃) 3.7(2H, s), 4.5 (2H, s),4.6(2H, m), 5.25(2H, m), 5.9(1H, m), 7.15-7.4(4H, dd)

b. Allyl 4-(acetylthiomethyl)phenyl acetate

Colourless oil, 96% yield. ¹ H NMR δ (CDCl₃) 2.36(3H, s), 3.6(2H, s),4.1(2H, s), 4.65(2H, m), 5.25(2H, m), 5.9(1H, m), 7.23(4H, dd)

c. 4-(4-Allyloxycarbonylmethyl)benzylthio)azetidin-2-one

Yellow oil, 69% yield. ¹ H NMR δ (CDCl₃) 2.81-2.88(1H, dd),3.26-3.35(1H, dd), 3.65(2H, s), 3.83(2H, s), 4.6(2H, m), 4.68(1H, dd),5.20-5.32(2H, m), 5.60(1H, broad) 5.8-6.0(1H, m), 7.21-7.31(4H, dd)

Literature references for other amines:

6-phenylhexylamine

Morse M. A. et al., Cancer Research, 1991, 1846

6-(4-Chlorophenyl)hexylamine

Lamattine J. L. EP 138464 A2 850424 (CA 103:142000)

6-(4-hydroxyphenyl)hexylamine

Goodwin B. L. et al., Xenobiotica, 1994, 24(2), 129

4-Acetoxyzetidin-2-one

Clauss K et al., Annalen, 1974, 539

EXAMPLES Example 1 4-(Benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one

a. 4-(Benzylthio)azetidin-2-one

Sodium (8.1 g, 0.35 mol) was dissolved in ethanol (250 ml) and benzylmercaptan (45.2 g, 0.37 mol) added dropwise over 20 minutes keeping thetemperature between 20° C.-25° C. whilst bubbling nitrogen through themixture. After 15 minutes, the reaction was cooled to 5° C. and asolution of 4-acetoxyazetidin-2-one (45.0 g, 0.35 mol) in ethanol (50ml) was added dropwise over 15 minutes whist maintaining the temperatureat 5° C. The mixture was stirred at room temperature for 60 minutes andevaporated to dryness under reduced pressure. Water (500 ml) was added,the mixture extracted with dichloromethane (2×300 ml), the extractsdried (MgSO₄) and evaporated under reduced pressure to an oil. The oilwas cooled to -20° C. and titurated with ether (400 ml) to give a whitesolid which was isolated by filtration (50.2 g, 79%), mp 50-51.0° C.

¹ NMR δ (CDCl₃) 2.86(1H, m, H_(3a)), 3.30(1H, m, H_(3b)), 3.85 (2H, s,SCH₂), 4.68 (1H, m, H₄), 7.31 (5H, m, Ph-H).

b. 4-(Benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one

To a cooled (cold water bath) solution of 4-(benzylthio)azetidin-2-one(5.5 g, 28.5 mmol), tetra-n-butylammonium bromide (0.9 g, 2.85 mmol) and1-bromo-4-phenylbutan-2-one (7.1 g, 31.3 mmol) in dry THF (100 ml) wasadded freshly powdered potassium hydroxide (1.8 g, 31.3 mmol), and themixture stirred vigorously for 2 hr at ambient temperature. Water wasadded and the product extracted into ethyl acetate, dried (MgSO₄) andevaporated to an oil. Treatment with ether gave the product as a whitecrystalline solid (3.12 g, 32%) mp 79-81° C.

¹ H NMR δ (CDCl₃), 2.58 (2H, m, CH₂ CO), 2.86 (2H, t, J=7.5 Hz, CH₂ Ph),2.96 (1H, dd, J=2.2, 15.2 Hz, H_(3a), ), 3.17, 3.98 (each 1H, d, J=18.5Hz, NCH₂), 3.43 (1H, dd, J=5.1, 15.2 Hz, H_(3b)), 3.70 (2H, s, SCH₂),4.89 (1H, dd, J=2.4, 5.1 Hz, H₄), 7.15-7.33 (10 H, m, Ph-H).

Found: C, 70.9; H, 6.3; N, 4.3%; C₂₀ H₂₁ NO₂ S requires: C, 70.8; H,6.2; N, 4.1%

EXAMPLE 2 (4R,SR/4S,SS)4-(Benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one

A solution of 4-(benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one (3.1g, 9.2 mmol) in dichloromethane (100 ml) was cooled to -50 to -60° C.and a solution of m-chloroperbenzoic acid (1.9 g, 11 mmol) indichloromethane (80 ml) added dropwise with stirring over 30 min. Aftera further 30 min at -50 to -60° C. the reaction mixture was shaken witha mixture of saturated aqueous sodium sulphite and saturated sodiumhydrogen carbonate and the organic layer separated, dried (MgSO₄) andevaporated to a solid. Two recrystallisations from ethyl acetate gave(4R,SR/4S,SS) 4-(benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one(0.8 g, 27%), mp 147-9° C.

¹ H NMR δ (CDCl₃), 2.71 (2H, m, CH₂ CO), 2.89 (2H, m, CH₂ Ph), 2.93 (1H,dd, J=4.7, 14.8 Hz, H_(3a)), 3.36 (1H, dd, J=1.8, 14.8 Hz, H_(3b)),3.72, 4.37 (each 1H, d, J=18.9 Hz, NCH₂), 3.9 (2H, s, CH₂ SO), 4.70 (1H,dd, J=2.2, 4.7 Hz, H₄), 7.12-7.40 (10H, m, Ph-H).

Found: C, 67.5; H, 6.0; N, 4.0%; C₂₀ H₂₁ NO₃ S requires: C, 67.6; H,6.0; N, 3.9%

EXAMPLE 3 (4R,SS/4S,SR)4-(Benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one

The combined filtrates from the above crystallisations were evaporatedand the residue recrystallised twice from ethanol to give apredominantly (4R,SS/4S,SR)4-(benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one (1.2 g, 37%),mp 110-11° C.

1H NMR δ (CDCl₃), 2.45 (1H, dd, J=2.3, 15.4 Hz, H_(3a)), 2.71 (2H, m,CH₂ CO), 2.89 (2H, m, CH₂ Ph), 3.03 (1H, dd, J=5.1, 15.3 Hz, H_(3b)),3.94, 4.12 (each 1H,d, J=13.0 Hz, CH₂ SO), 4.19, 4.37 (each 1H, d,J=19.2 Hz, NCH₂), 4.65 (1H, dd, J=2.4, 5.1 Hz, H₄), 7.12-7.40 (10H, m,Ph-H).

Found: C, 67.5; H, 6.1; N, 4.1%, C₂₀ H₂₁ NO₃ S requires: C, 67.6; H,6.0; N, 3.9%

EXAMPLE 4 4-(Benzylsulphonyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

To a cooled (ice bath) solution of4-(benzylthio)-N-(4-phenyl-2-oxobutyl)azetidinone (0.6 g, 1.76 mmol) indichloromethane (25 ml) was added dropwise with stirring a solution ofm-chloroperoxybenzoic acid (0.92 g, 5.3 mmol) in dichloromethane (25ml). The ice bath was removed, and after 1.5 hr. the solution was washedwith a mixture of saturated aq. sodium hydrogen carbonate and saturatedaq. sodium sulphite. The aq. layer was back extracted withdichloromethane and the combined organic layers dried (MgSO₄) andevaporated to an oil which was crystallised from ether (0.56 g, 86%) mp131-3° C.

1H NMR δ (CDCl₃), 2.69 (2H, t, J=6.9 Hz, CH₂ CO), 2.9 (2H, m, CH₂ Ph),2.94 (1H, dd, J=2.1, 10.8 Hz, H_(3a)), 3.14 (1H, dd, J=5.1, 15.4 Hz,H_(3b)), 3.82, 4.35 (each 1H, d, J=18.8 Hz, NCH₂), 4.28 (2H, s, SO₂CH₂), 4.89 (1H, dd, J=2.3, 5.1 Hz, H₄), 7.14-7.43 (10H, m, Ph-H).

Found: C, 64.5; H, 5.8; N, 3.8%; C₂₀ H₂₁ NO₄ S requires: C, 64.7; H,5.7; N, 3.8%

The following compounds (Examples 5 to 25) were prepared using thegeneral procedures of Examples 1-4. Where shown, ratios indicate therelative diastereomeric proportion (4R,SR/4S,SS:4R,SS/4S,SR) asdetermined by ¹ H NMR.

EXAMPLE 5 4-(Benzythio)-1-(2-phenyl-2-oxoethyl)azetidin-2-one

Colourless oil, 48% yield.

1H NMR δ (CDCl₃) 3.02 (1H, dd, J=15.25, 2.00 Hz, H_(3a)), 3.27 (1H, dd,J=15.25, 5.15 Hz, H_(3b)), 3.72 (1H, d, J=21.76, COCH₂), 3.75 (2H, s,SCH₂), 4.70 (1H, d, J=18.3, COCH₂), 5.08 (1H, dd, J=5.13, 2.39, H₄),7.08-7.29 (5H, m, Ph-H), 7.44-7.50 (2H, m, Ph-H), 7.57-7.64 (1H, m,Ph-H), 7.76-7.80 (2H, m, Ph-H).

EXAMPLE 6 (4R,SR/4S,SS)4-(Benzylsulphinyl)-1-(2-phenyl-2-oxoethyl)azetidin-2-one

White solid, 11.5% yield, mp 130-31° C.

Found: C, 65.8; H, 5.2; N, 4.4%; C₁₈ H₁₇ NO₃ S requires: C, 66.0; H,5.2;N, 4.3%

EXAMPLE 7 (4R,SS/4S,SR)4-(Benzylsulphinyl)-1-(2-phenyl-2-oxoethyl)azetidin-2-one

White solid, dias. ratio 15:85, 15% yield, mp 92-93° C.

Found: C, 65.8; H, 5.3; N, 4.4%; C₁₈ H₁₇ NO₃ S requires: C, 66.0; H,5.2; N, 4.3%

EXAMPLE 8 4-(Benzylthio)-1-(9-phenyl-2-oxononyl)azetidin-2-one

a. 1-bromo-9-phenylnonan-2-one

A solution of 6-bromohexanoyl chloride (49.7 g, 0.233 mol) in drydichloromethane (40 ml) was added dropwise over 5 minutes to asuspension of aluminium chloride (31.0 g, 0.233 mol) in drydichloromethane (100 ml), keeping the temperature between 20° C.-23° C.The mixture was stirred for 30 minutes at room temperature to give ayellow solution. Benzene (18.2 g, 0.233 mol) in dry dichloromethane (30ml) was added and stirred for 20 hours at room temperature.Triethylsilane (59.9 g, 0.515 mol) was added over 10 minutes,maintaining the temperature between 25° C.-35° C. The solution wasstirred for 60 minutes at room temperature. This was then poured ontoice/water (200 g). A partial separation was achieved and the organiclayer was washed with brine and water several times until the pH of thesolution was neutral. The organic solution was dried (MgSO₄) andevaporated under reduced pressure to a yellow oil. This was distilledunder reduced pressure at 90° C.-110° C./0.5 mbar to give colourlessoils. The relevant fractions were combined and purified by flashchromatography on silica gel using hexane to give 6-bromo-1-phenylhexaneas a colourless oil (18.33 g, 33%).

6-Bromo-1-phenylhexane (18.02 g, 0.075 mol) was dissolved in acetone(300 ml), NaI (44.85 g, 0.299 mol) was added, and the mixture heated atreflux temperature for 18 hours. This was filtered and the acetoneevaporated under reduced pressure to give a residual mass which wasextracted with n-pentane (150 ml). The insoluble solid was filtered offand the filtrate evaporated to give 6-iodo-1-phenylhexane as acolourless liquid (21.22 g, 99%).

6-Iodo-1-phenylhexane (17.43 g, 0.061 mol), acetyl acetone (6.66 g,0.067) and potassium carbonate (8.41 g, 0.061 mol) were dissolved in dryabsolute ethanol (75 ml) and the solution was refluxed for 18 hours.After cooling to room temperature the solution was filtered andevaporated under reduced pressure to an oil. This was partitionedbetween ethyl acetate (80 ml) and water (80 ml), and the organic layerwas washed with brine, dried and evaporated to an orange oil (15.27 g).This was purified by flash chromatography on silica gel using petroleumether/ethyl acetate to give 9-phenylnonan-2-one as a colourless oil(7.12 g, 54%).

Bromine (5.21 g, 0.033 mol) was added to a solution of9-phenylnonan-2-one (7.12 g, 0.033 mol) in dry methanol (75 ml) andstirred for 2 hours at room temperature. Water (50 ml) was added andstirring continued for 18 hours at room temperature. Ether (175 ml) andwater (100 ml) were added, the organic layer washed with dil. NaHCO₃,water (×2), dried (MgSO₄) and evaporated under reduced pressure to anoil (5.39 g). Petroleum ether (40° C.-60°C., 50 ml) was added and themixture cooled to -10° C. and filtered. The solid obtained wasre-dissolved in ether (40 ml) and evaporated under reduced pressure toan oil (4.06 g) which was was further purified by flash chromatographyon silica gel using hexane/ethyl acetate to give1-bromo-9-phenylnonan-2-one a pale yellow solid (3.80 g, 39%).

b. 4-(Benzylthio)-1-(9-phenyl-2-oxononyl)azetidinone

Colourless oil, 66% yield, ¹ H NMR δ (CDCl₃), 1.3 (6H, m, (CH₂)₃), 1.55(4H, m, CH₂ CH₂ Ph, CH₂ CH₂ CO), 2.24, (2H, m, CH₂ CO), 2.60 (2H, t,J=7.5 Hz, CH₂ Ph), 2.97 (1H, dd, J=2.2 , 15.2 Hz, H_(3a)), 3.21, 4.01(each 1H, d, J=18.6 Hz, NCH₂), 3.43 (1H, dd, J=5.1, 15.2 Hz, H_(3b)),3.73 (2H, s, SCH₂), 4.93 (1H, dd, J=2.4, 5.1 Hz, H₄), 7.14-7.35 (10H, m,Ph-H).

EXAMPLE 9 (4R,SR/4S,SS)4-(Benzylsulphinyl)-1-(9-phenyl-2oxononyl)azetidin-2-one

Colourless solid, 25% yield, mp 133-5° C., 1H NMR δ (CDCl₃), 1.30 (m,6H, (CH₂)₃), 1.58 (4H, m, CH₂ CH₂ Ph, CH₂ CH₂ CO), 2.37 (2H, t, J=7.5Hz, CH₂ CO), 2.59 (2H, t, J=7.9 Hz, CH₂ Ph), 2.94 (1H, dd, J=4.7, 14.8Hz, H_(3a)), 3.36 (1H, dd, J=1.7, 14.9 Hz, H_(3b)), 3.79, 4.42 (each 1H,d, J=18.9 Hz, NCH₂), 3.91 (2H, s, SOCH₂), 4.77 (1H, dd, J=2.2, 4.7 Hz,H₄), 7.15-7.4 (10H, m, Ph-H). Found: C, 70.3; H, 7.2; N, 3.4%; C₂₅ H₃₁NO₃ S requires: C, 70.6; H, 7.3; N, 3.3%.

EXAMPLE 10 (4R,SS/4S,SR)4-(Benzylsulphinyl)-1-(9-phenyl-2-oxononyl-azetidin-2-one

Dias. Ratio 1:0, Colourless solid, 30% yield, mp 75-6° C., 1H NMR δ(CDCl₃), 1.3 (m, 6H, (CH₂)₃), 1.58 (4H, m, CH₂ CH₂ Ph, CH₂ CH₂ CO), 2.34(2H, t, J=7.6 Hz, CH₂ CO), 2.43 (1H, dd, J=2.3, 15.2 Hz, H_(3a)), 2.59()2H, t, J=7.4 Hz, CH₂ Ph), 3.02 (1H, dd, J=5.1 15.3 Hz, H_(3b)), 3.94,4.13 (each 1H, d, J=13.0 Hz, SOCH₂), 4.19, 4.38 (each 1H, d, J=18.7 Hz,NCH₂), 4.65 (1H, dd, J=2.4, 5.1 Hz. H₄), 7.14-7.43 (10H, m, Ph-H).Found: C, 70.4; H, 7.3; N, 3.4%; C₂₅ H₃₁ NO₃ S requires: C, 70.6; H,7.3; N, 3.3%.

EXAMPLE 11 4-(2-Methoxybenzylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Colourless oil, 62% yield, 1H NMR δ (CDCl₃), 2.60 (2H, m, CH₂ CO), 2.87(2H, t, J=7.5 Hz, CH₂ Ph), 3.01 (1H, dd, J=2.2, 15.2 Hz, H_(3a)), 3.23,4.00 (each 1H, d, J=18.6 Hz, NCH₂), 3.43 (1H, dd, J=5.1, 15.2 Hz,H_(3b)), 3.72 (2H, d, J=2.4 Hz, SCH₂), 3.83 (3H, s, OCH₃), 4.95 (1H, dd,J=2.4, 5.1 Hz, H₄) 6.81-6.92 (2H, m, 3,5-(2-CH₃ OPh)-H), 7.15-7.32 (7H,m, 4,6-(2-CH₃ OPh)-H, Ph-H).

EXAMPLE 12 (4R,SR/4S,SS)4-(2-Methoxybenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, 8% yield, mp 90-2° C. 1H NMR δ (CDCl₃), 2.71(12H, m, CH₂ CO), 2.88 (2H, m, CH₂ Ph), 3.00 (1H, dd, J=4.7, 14.8 Hz,H_(3a)), 3.46 (1H, dd, J=1.9, 14.8 Hz, H_(3b)), 3.70, 4.35 (each 1H, d,J=18.4 Hz, NCH₂), 3.88 (3H, s, OCH₃), 4.00(2H, s, SCH₂), 4.75 (1H, dd,J=2.2, 4.7 Hz, H₄), 6.90-7.38 (9H, m, PhH+CH₃ OPh-H). Found: C, 65.3; H,6.0; N, 3.9%; C₂₁ H₂₃ NO₄ S requires: C, 65.4; H, 6.0; N, 3.6%.

EXAMPLE 13 (4R,SS/4S,SR)4-(2-Methoxybenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Colourless oil, dias. ratio 1:3, 25% yield 1H NMR δ (CDCl₃), 2.49 (1H,dd, J=2.2, 15.4 Hz, H_(3a)), 2.71 (2H, m, CH₂ CO), 2.89 (2H, m, CH₂ Ph),3.04 (1H, dd, J=5.1, 15.4 Hz, H_(3b)), 3.87 (3H, s, OCH₃), 4.09 (2H, s,SCH₂), 4.19, 4.36 (each 1H, d, J=18.6 Hz, NCH₂), 4.69 (1H, dd, J=2.3,5.0 Hz, H₄), 6.89-7.34 (9H, m, Ph-H+CH₃ OPh-H). Found: C, 64.8; H, 6.1;N, 3.8%; C₂₁ H₂₃ NO₄ S.0.17H₂ O requires: C, 64.9; H, 6.1; N, 3.6%.

EXAMPLE 14 4-(4-Fluorobenzylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Colourless oil, 41% yield, 1H NMR δ (CDCl₃), 2.64 (2H, m, CH₂ CO), 2.88(2H, t, J=7.5 Hz, CH₂ Ph), 2.95 (1H, dd, J=2.3, 15.3 Hz, H_(3a)), 3.3,4.06 (each 1H, d, J=18.6 Hz, NCH₂), 3.42 (1H, dd, J=5.1, 15.3 Hz,H_(3b)), 3.67 (2H, s, SCH₂), 4.88 (1H, dd, J=2.4, 5.1 Hz, H₄), 6.84-7.33(9H, m, Ph-H, 4-FPh-H).

EXAMPLE 15 (4R,SR/4S,SS)4-(4-Fluorobenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, 16% yield, mp 152-4° C. 1H NMR δ (CDCl₃), 2.74(2H, t, J=7.0 Hz, CH₂ CO), 2.90 (2H, t, J=6.8 Hz, CH₂ Ph), 2.95 (1H, dd,J=4.7, 14.8 Hz, H_(3a)), 3.35 (1H, dd, J=1.8, 14.8 Hz, H_(3b)), 3.76,4.40 (each 1H, d, J=18.9 Hz, NCH₂), 3.85 (2H, m, SCH₂), 4.73 (1H, dd,J=2.2, 4.7 Hz, H₄), 7.04-7.32 (9H, m, Ph-H, 4-FPh-H). Found: C, 64.2; H,5.4; N, 3.9%; C₂₀ H₂₀ FNO₃ S requires: C, 64.3; H, 5.4; N, 3.8%.

EXAMPLE 16 (4R,SS/4S,SR)4-(4-Fluorobenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, 26% yield, mp 114-6° C. 1H NMR δ (CDCl₃), 2.60(1H, dd, J=2.3, 15.2 Hz, H_(3a)), 2.71 (2H, m, CH₂ CO), 2.91 (2H, m CH₂Ph), 3.15 (1H, dd, J=5.1, 15.2 Hz, H_(3b)), 3.96 (2H, m, SCH₂), 4.19,4.38 (each 1H, d, J=18.7 Hz, NCH₂), 4.65 (1H, dd, J=2.4, 5.1 Hz, H₄),7.05-7.33 (9H, m, Ph-H, 4-FPh-H). Found: C, 64.1; H, 5.5; N, 3.9%; C₂₀H₂₀ FNO₃ S requires: C, 64.3; H, 5.4; N, 3.8%.

EXAMPLE 17 4-(4-Methoxybenzylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystals, 74% yield, mp 70-71° C. 1H NMR δ (CDCl₃) 2.60 (1H, t,J=7.13 Hz, CH₂ Ph), 2.86 (1H, t, J=7.59 Hz, COCH₂), 2.96 (1H, dd,J=15.25, 2.20 Hz, H_(3a)), 3.24 (1H, d, J=18.53 Hz, NCH₂), 3.42 (1H, dd,J=15.25, 5.11 Hz, H_(3b)), 3.66 (2H, s, SCH₂), 3.76 (3H, s, OCH₃), 4.02(1H, d, J=18.53 Hz, NCH₂), 4.88 (1H, dd, J=5.10, 2.39 Hz, H₄), 6.79-6.84(2H, m, Ph-H), 7.16-7.32 (7H, m, Ph-H).

EXAMPLE 18 (4R,SR/4S,SS)4-(4-Methoxybenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, 20% yield, mp 155-157° C. Found: C, 64.5; H,6.0; N, 3.5%; C₂₁ H₂₃ NO₄ S 0.3 H₂ O requires: C, 64.5; H, 6.1; N, 3.6%.

EXAMPLE 19 (4R, SS/4S,SR)4-(4-Methoxybenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, 80% above diast., mp 92-93° C., 31% yield,Found: C, 64.7; H, 6.0; N, 3.5%. C₂₁ H₂₃ NO₄ S 0.2 H₂ O requires: C,64.8; H, 6.1; N, 3.6%.

EXAMPLE 20 4-(Phenethylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Colourless oil, 80% yield, 1H NMR δ (CDCl₃) 2.65-2.97 (9H, m, S--CH₂CH₂, COCH₂ CH₂, H_(3a)), 3.39 (1H, dd, J=15.22, 5.00 Hz, H_(3b)), 3.50and 4.17 (1H each, d, J=18.48 Hz, N--CH₂), 4.83 (1H,. dd, J=4.99, 2.34Hz, H₄), 7.14-7.33 (10H, m, Ph-H).

EXAMPLE 21 (4R, SR/4S,SS)4-(Phenethylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, 8% yield, mp 163-165° C. Found: C, 68.0; H,6.2; N, 4.0%; C₂₁ H₂₃ NO₃ S requires: C, 68.3; H, 6.3; N, 3.8%.

EXAMPLE 22 4R,SS/4S,SR)4-(Phenethylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, 14.5% yield, mp 91-92° C. Found: C, 68.08; H,6.32; N, 3.86%; C₂₁ H₂₃ NO₃ S requires: C, 68.3; H, 6.3; N, 3.8%.

EXAMPLE 23 4-(3-Phenylpropylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Colourless oil, 67% yield, 1H NMR δ (CDCl₃), 1.87 (2H, m, SCH₂ CH₂),2.47 (2H, m, CH₂ CO), 2.72 (4H, m, 2xCH2Ph), 2.9 (2H, t, J=7.1 Hz, CH₂S), 2.96 (1H, dd, J=2.2, 15.2 Hz, H_(3a)), 3.48 (1H, dd, J=5.0, 15.2 Hz,H_(3b)), 3.63, 4.23 (each 1H, d, J=18.5 Hz, NCH₂), 4.86 (1H, dd, J=2.3,5.0 Hz, H₄), 7.14-7.32 (10H, m, Ph-H).

EXAMPLE 24 (4R,SR/4S,SS)4-(3-Phenylpropylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, 25% yield, mp 136-8° C. 1H NMR δ (CDCl₃), 2.11(2H, m, SOCH₂ CH₂), 2.49 (2H, m, SOCH₂), 2.78 (4H, m, 2xCH2Ph), 2.91(2H, m, CH₂ CO), 3.15 (1H, dd, J=4.8, 14.7 Hz, H_(3a)), 3.55 (1H, dd,J=1.7, 14.7 Hz, H_(3b)), 3.78, 4.44 (each 1H, d, J=18.9 Hz, NCH₂), 4.66(1H, dd, J=2.2, 4.8 Hz, H₄), 7.14-7.35 (10H, m, Ph-H). Found: C, 68.6;H, 6.4; N, 3.8%; C₂₂ H₂₅ NO₃ S requires: C, 68.9; H, 6.6; N, 3.7%.

EXAMPLE 25 4R, SS/4S,SR)4-(3-Phenylpropylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, 13% yield, mp 65-6° C. 1H NMR δ (CDCl₃), 2.12(2H, m, SOCH₂ CH₂), 2.54 (2H, m, SOCH₂), 2.55-2.94(7H, m, 2xCH2Ph+CH₂CO+H_(3a)), 3.33 (1H, dd, J=5.2, 15.1 Hz, H_(3b)), 4.20, 4.40 (each 1H,d, J=18.7 Hz, NCH₂), 4.66 (1H, dd, J=2.2, 4.8 Hz, H₄), 7.14-7.35 (10H,m, Ph-H). Found: C, 68.6; H, 6.5; N, 3.9%; C₂₂ H₂₅ NO₃ S requires: C,68.9; H, 6.6; N, 3.7%.

EXAMPLE 26 trans3-Methyl-4-(benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one

A solution of trans-3-methyl-4-(benzylthio)azetidin-2-one (0.73 g, 3.5mmol) in dry THF (5 ml) was added dropwise over 5 minutes to asuspension of sodium hydride (60% dispersion in oil, 0.15 g, 3.8 mmol)in dry THF (10 ml) under a nitrogen atmosphere at -10° C. The mixturewas stirred for 10 minutes at -10° C. and 1-bromo-4-phenylbutan-2-one(0.79 g, 3.5 mmol) in dry THF (10 ml) was added over 5 minutes at -10°C. The mixture was stirred at room temperature for 30 minutes and pouredinto ice/water. The layers were separated and the aqueous was extractedwith ethyl acetate. The combined organics were washed with brine, dried(MgSO₄) and evaporated to an oil. This was purified by flashchromatography on silica gel eluting with petroleum ether 40-60°C./ethyl acetate 3:1, 2:1 to give a colourless solid (0.34 g, 27%) mp69-71° C.

¹ H NMR δ (CDCl₃) 1.34 (3H, d, J=7 Hz, SCH₃), 2.55 (2H, m, CH₂ Ph), 2.85(2H, t, J=8 Hz, COCH₂ CH₂), 3.11, 3.97 (each 1H, d, J=18 HZ, NCH₂), 3.15(1H, m, H₃), 3.70 (2H, m, SCH₂), 4.50 (1H, d, J=2 Hz, H₄), 7.1-7.4 (10H,m, 2xPh-H).

EXAMPLE 27 (4R,SR/4S,SS) trans3-Methyl-4-(benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one

Prepared from trans3-methyl-4-(benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one using thegeneral procedure of Example 2 and obtained as a white solid, 40% yield,mp 87-94° C.

¹ H NMR δ (CDCl₃) 1.23 (3H, d, J=7 Hz, CH₃), 2.71 (2H, m, CH₂ Ph), 2.9(3H, m, COCH₂ +H₃), 3.91, 4.09 (each 1H, d, J=13 Hz, SOCH₂), 4.17, 4.39(each 1H, d, J=19 Hz, NCH₂), 4.38 (1H, d, J=2 Hz, H₄), 7.1-7.4 (10H, m,Ph-H). Found: C, 68.1; H, 6.3; N, 4.0%; C₂₁ H₂₃ NO₃ S requires: C, 68.3;H, 6.3; N, 3.8%.

EXAMPLE 28 (4R,SS/4S,SR) trans3-Methyl-4-(benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one

Prepared from trans3-methyl-4-benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one using thegeneral procedure of Examples 2 and 3 and obtained as a white solid,dias. ratio 1:4, 19% yield, mp 114-7° C.

¹ H NMR δ (CDCl₃) 1.43 (3H, d, J=8 Hz, CH₃), 2.7 (2H, m, CH₂ Ph), 2.9(2H, m, COCH₂), 3.65, 4.37 (each 1H, d, J=19 Hz, NCH₂), 3.82 (1H, m,H₃), 3.93 (2H, m, SOCH₂), 4.44 (1H, d, J=2 Hz, H₄), 7.1-7.4 (10H, m,Ph-H), Found: C, 68.1; H, 6.3; N, 4.0%; C₂₁ H₂₃ NO₃ S requires; C, 68.3;H, 6.3; H, 3.8%.

EXAMPLE 29 N-(6-phenylhexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

a. Methyl-(4-benzylthio-2-oxoazetidin-1-yl) Acetate

To a solution of 4-benzylthio)azetidin-2-one (5.0 g, 25 mmol), methylbromoacetate (4.6 g, 30 mmol) and tetrabutylammonium bromide (0.9 g,0.28 mmol) in dry THF (150 ml) was added powdered potassium hydroxide(1.7 g, 30 mmol). The resulting mixture was stirred for two hours atroom temperature before water (50 ml) was added. The solution wasextracted with ethyl acetate (3×150 ml portions) and the combinedextracts dried (MgSO₄) and evaporated. The residue was purified by flashchromatography on silica gel eluted with petroleum ether 60°-80°:ethylacetate 4:1 to give methyl (4-benzylthio-2-oxoazetidin-1-yl)acetate as ayellow oil (5 g, 70%). ¹ H NMR δ (CDCl₃) 2.96(1H, dd, J=2.5, 16 HzH_(3a)), 3.24, 3.99 (each 1H, d, J=18.00 Hz, NCH₂), 3.4 (1H, dd, J=5,12.5 Hz H_(3b)), 3.70 (3H, s, OCH₃), 3.77 (2H, s, SCH₂), 4.92 (1H, m,H₄), 7.28 (5H, m, Ph-H).

b. (4-Benzylthio-2-oxoazetidin-1-yl)acetic Acid

To a solution of methyl (4-benzylthio-2-oxo-azetidin-1-yl)acetate (2.5g, 9.4 mmol) in methanol (80 ml) was added, dropwise at 0° C., asolution of 1 N sodium hydroxide (9.9 ml, 9.9 mmol). The reaction wasstirred for 1 hr and evaporated to dryness. Water (50 ml) was added andthe solution acidified to pH 3 with dilute hydrochloric acid andextracted with ethyl acetate (3×100 ml). The combined extracts weredried (MgSO₄), evaporated and the residue purified by recrystallisation(hexane/ether) to give (4-benzylthio-2-oxo-azetidin-1-yl)acetic acid asa white solid (1.3 g, 55%), mp 110-110° C. ¹ H NMR δ (CDCl₃) 2.99 (1H,dd, J=6.87, 17.5 Hz, H_(3a)), 3.27, 4.06 (each 1H, d, J=18.40 Hz, NCH₂),3.39 (1H, dd, J=5, 15.4 Hz, H_(3b)), 3.77 (2H, s, SCH₂), 4.91 (1H, m,H₄), 7.27 (5H, m, Ph-H).

c. N-(6-phenylhexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

A solution of 6-phenylhexylamine (Morse M. A. et al., Cancer Research,1991, 1846), (7.0 g, 40 mmol) in DMF (20 ml) was added to DCC (8.2 g, 40mmol), hydroxybenzotriazole (5.3 g, 39 mmol) and(4-benzylthio-2-oxoazetidin-1-yl)acetic acid (10 g, 39 mmol) and themixture stirred for 2 hours at room temperature. Ethyl acetate (250 ml)was added, the precipitate filtered, the filtrate washed with dilNaHCO₃, water (×2), dried (MgSO₄) and evaporated to an oil which waspurified by flash chromatography on silica gel using hexane/ethylacetate (1:1). Evaporation of the appropriate fractions followed bytreatment with hexane gave a white solid (11.2 g, 70%), mp 65-70° C.

EXAMPLE 30 (4R,SR/4S,SS)N-(6-phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

A solution of N-(6-phenylhexyl)-4-benzylthio-2-oxoazetidin-1-ylacetamide (18.0 g, 43.8 mmol) in dichloromethane (500 ml) was cooled to-70° C. and a solution of m-chloroperbenzoic acid (6.7 g, 43.8 mmol) indichloromethane (500 ml) added dropwise with stirring over 60 min. Aftera further 3 h at -60° C., the reaction mixture was shaken with a mixtureof saturated aqueous sodium sulphite and saturated sodium hydrogencarbonate. The organic layer was separated, washed with brine, dried(MgSO₄) and evaporated to a solid which was titurated with ether andfiltered. Two recrystallisations from ethyl acetate gave (4R,SR/4S,SS)N-(6phenylhexyl)-4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (3.8 g,20%) mp 138-140° C.

Found: C, 64.4; H, 6.9; N, 6.8%; C₂₄ H₃₀ N₂ O₃ S requires: C, 67.6; H,7.1; N, 6.6%.

EXAMPLE 31 (4R, SS/4S,SR)N-(6-phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

The above filtrate was diluted with hexane, filtered and upon standingdeposited the title compound as a colourless crystalline solid (4.5 g,24%), mp 107-108° C.

Found: C, 67.4; H, 7.1; N, 6.8%; C₂₄ H₃₀ N₂ O₃ S required: C, 67.6; H,7.1;N, 6.6%.

The following compounds (Examples 32 to 57) were prepared using thegeneral procedure of Examples 29-31. Where shown, ratios indicate therelative diastereomeric proportion (4R,SR/4S,SS:4R, SS/4S/SR) asdetermined by ¹ H NMR.

EXAMPLE 32 N-benzyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

White solid, 49% yield, mp 89-90° C., ¹ H NMR δ (CDCl₃) 2.94 (1H, dd,J=2.5, 5.25 Hz, H_(3a)), 3.37 (1H, dd, J=2.5, 5 Hz, H_(3b)), 3.65, 3.76(each 1H, d, J=15.0 Hz, NCH₂), 3.76 (2H, s, SCH₂), 4.4 (2H, m, NHCH₂),4.81 (1H, m, H₄), 6.33 (1H, bs, NH), 7.20-7.37 (10H, m, Ph-H).

EXAMPLE 33 (4R,SR/4S,SS)N-benzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White crystalline solid, 8% yield, mp 192-193° C., Found: C, 63.8; H,5.7; N, 8.0%, C₁₉ H₂₀ N₂ O₃ S requires: C, 64.0; H, 5.7; N, 7.9%.

EXAMPLE 34 (4S, SS/4S,SR)B-benzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, dias. ratio 15:85, 36% yield, mp 181-182° C. Found: C,63.4; H, 5.5; N, 7.7%; C₁₉ H₂₀ N₂ O₃ S 0.2 H₂ O requires: C, 63.5; H,5.7; N, 7.8%.

EXAMPLE 35 N-(4-Phenylbutyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Colourless oil, 100% yield. ¹ H NMR δ (CDCl₃) 1.5-1.7 (4H, m, CH₂ CH₂),2.63 (2H, t, J=7 Hz, CHhd 2Ph), 2.93 (1H, dd, J=2, 15 Hz, H₃), 3.26 (2H,m, NCH₂), 3.36 (1-H, dd, J=5, 15 Hz, H₃), 3.53, 3.70 (each 1H, d, J=17Hz, NCH₂), 3.79 (2H, s, SCH₂), 4.80 (1H, m, H₄), 6.07 (1H, br s, NH),7.1-7.4 (1H, m, 2xPh-H).

EXAMPLE 36 (4R,SR/4S,SS)N-(4-{Phenylbutyl)-4-benzylsulphinyl-2-oxoazetidin-1yl)acetamide

White solid, dias. ratio 4:1, 15% yield, mp 161-2° C. ¹ H NMR δ (CDCl₃)1.5-1.7 (4H, m, CH₂ CH₂) 2.62 (2H, t, J=7 Hz, CH₂ Ph), 2.95 (1H, dd,J=5, 15 Hz, H₃), 3.26 (2H, m, NHCH₂), 3.4 5(1H, dd, J=2, 15 Hz, H₃),3.71, 4.10 (each 1H, d, J=17 Hz, NCH₂), 3.88, 4.04 (each 1H, d, J=13 Hz,SOCH₂), 4.51 (1H, m, H₄), 6.65 (1H, br s, NH), 7.1-7.4 (1H, m, 2xPh-H),Found: C, 66.2; H, 6.5; N, 7.0%; C₂₂ H₂₆ N₂ O₃ S requires: C, 66.3; H,6.6; N, 7.0%.

EXAMPLE 37 (4R, SS/4S,SR)N-(4-Phenylbutyl)-4-(benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, dias. ratio 5:95, 30% yield, mp 107-8° C. ¹ H NMR δ (CDCl₃)1.5-1.7 (4H, m, CH₂ CH₂), 2.63 (2H, t, J=7 Hz, CH₂ Ph), 2.85 (1H, dd,J=2, 15 Hz, H.sub.), 3.15 (1H, dd, J=5, 15 Hz, Hhd 3), 3.3 (2H, m,NHCH₂), 3.90, 4.23 (each 1H, d, J=17 Hz, NCH₂), 3.97, 4.15 (each 1H, d,J=13 Hz, SOCH₂), 4.60 (1H, m, H₄), 7.1-7.4 (11H, m, 2xPh-H+NH), Found:C, 66.1; H, 6.5; N, 7.1%; C₂₂ H₂₆ N₂ O₃ S requires: C, 66.3; H, 6.6; N,7.0%.

EXAMPLE 38 N-(9-Phenylnonyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Colourless oil, 84% yield. ¹ H nmr δ (CDCl₃) 1.28-1.48 (14H, m, 7xCH₂),2.59 (2H, t, J=7.7 Hz, PhCH₂), 2.92, 2.98 (1H, dd, J=2.5, 15.4 Hz, H₃),3.2 (2H, m, NHCH₂), 3.34, 3.40 (1H, dd, J=5.2, 15.4 Hz, H₃), 3.56, 3.72(each 1H, d, J=16.8 Hz, NCH₂), 3.81 (2H, s, SCH₂), 4.81 (1H, m, H₄), 6.0(1H, m, NH), 7.2 (10H, m, 2xPh-H).

EXAMPLE 39 (4R,SR/4S,SS)N-(9-Phenylnonyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, dias. ratio 4:1, 8% yield, mp 124-128° C. ¹ H nmr δ (CDCl₃)1.2-1.7 (14H, m, 7xCH₂), 2.59 (2H, t, J=7.8 Hz, PhCH₂), 2.93, 2.97 (1H,dd, J=4.8, 14.8 Hz, H₃), 3.23 (2H, m, NHCH₂), 3.44, 3.48 (1H, dd, J=2.4,14.8 Hz, H₃), 3.7, 4.1 (each 1H, d, J=17.2 Hz, NCH₂), 3.9, 4.13 (each1H, d, J=12.8 Hz, SOCH₂), 4.5 (1H, m, H₄), 6.59 (1H, m, NH), 7.16-7.41(10H, m, 2xPh-H), Found: C, 68.9; H, 7.5; N, 5.6%; C₂₇ H₃₆ N₂ O₃ Srequires: C, 69.2; H, 7.7; N, 6.0%.

EXAMPLE 40 (4R,SS/4S,SR)N-(9-phenylnonyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, dias. ratio 4:6, 48% yield, mp 123-128° C., ¹ H nmr δ(CDCl₃) 1.2-1.7 (14H, m, 7xCH₂), 2.59 (2H, t, J=7.8 Hz, PhCH₂),2.85-2.97 (1H, m H₃), 3.1-3.5 (3H, m, NHCH₂, H₃), 3.7-4.2 (4H, m, SOCH₂,NCH₂), 4.5-4.6 (1H, 2×m, H₄), 6.68 (m, NH'), 7.17-7.42 (1H, m, 2xPh-H),Found: C 69.3; H, 7.8; N, 6.1%; C₂₇ H₃₆ N₂ O₃ S requires: C, 69.2; H,7.7; N, 6.0%.

EXAMPLE 41N-Methyl-N-(6-phenylhexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Yellow oil, 88% yield. ¹ H nmr δ (DMSO-d₆ 350K) 1.24-1.57 (8H, m,4xCH₂), 2.55 (2H, m, PhCH₂), 2.79-2.95 (4H, m, NCH₃, H₃), 3.1-3.3 (2H,m, NCH₂), 3.32, 3.35 (1H, dd, J=5.2, 14.8 Hz, H₃), 3.45, 4.09 (each 1H,d, J=16.8 Hz, NCH₂ C═O), 3.84 (2H, s, SCH₂), 4.94 (1H, m, H₄), 7.14-7.32(10H, m, 2xPh-H).

EXAMPLE 42 (4R,SR/4S,SS)N-Methyl-N-(6-phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

Colourless oil, dias. ratio 55:45, 67% yield, ¹ H NMR δ (DMSO-d₆ 350K)1.2-1.6 (8H, m, 4xCH₂), 2.56 (2H, t, J=7.6 Hz, PhCH₂), 2.86(4H, m, NCH₃,H₃), 3.02-3.26 (m, NCH₂ CH₂, H₃), 3.81-4.4 (4H, m, SOCH₂, NCH₂ C═O),4.81, 4.90 (1H, 2×m, H₄), 7.12-7.35 (10H, m, 2xPh-H), Found: C, 65.4; H,6.9; N, 6.3%; C₂₅ H₃₂ N₂ O₃ S requires: C, 68.1; H, 7.3: N, 6.4%.

EXAMPLE 43 (4R,SS/4S,SR)N-Methyl-N-(6phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

Colourless oil, 13% yield, ¹ H nmr δ (DMSO-d₆ 350K) 1.2-1.6 (8H, m,4xCH₂), 2.56 (2H, t, J=7.6 Hz, PhCH₂), 2.86 (4H, m, NCH₃, H₃), 3.1-3.3(m, NCH₂, H₃), 4.01 (2H, m, SOCH, NCHC═O), 4.17 (1H, d, J=12.9 Hz,SOCH), 4.37 (2H, d, J=17.4 Hz, NCHC═O), 4.81 (1H, m, H₄), 7.13-7.35 (1H,m, 2xPh-H), Found: C, 65.3; H, 6.8; N, 6.1%; C₂₅ H₃₂ N₂ O₃ S requires:C, 68.1; H, 7.3: N, 6.4%.

EXAMPLE 44N-[6-(3,5-di-tert-butyl-4-hydroxyphenyl)hexyl]-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Yellow oil, 83% yield, ¹ H NMR δ (CDCl₃) 1.3-1.6 (26H, m, 4xCH₂ +6xCH₃),2.50 (2H, t, J=8 Hz, CH₂ Ph), 2.95 (1H, dd, J=2, 15 Hz, H₃), 3.25 (2H,q, J=7 Hz, NHCH₂), 3.37 (1H, dd, J=5, 15 Hz, H₃), 3.55, 3.71 each 1H, d,J=17 Hz, NCH₂), 3.82 (2H, s, SCH₂), 4.80 (1H, m, H₄), 5.03 (1H, s, OH),6.02 (1H, br s, NH), 6.96 (2H, s, HOPh-H), 7.3 (5H, m, Ph-H).

EXAMPLE 45 (4R,SS/4S,SR)N-[6-(3,5-Di-tert-butyl-4-hydroxyphenyl)hexyl]-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

Light brown glass, 33% yield, ¹ H NMR δ (CDCl₃) 1.3-1.7 (26H, m 4xCH₂+6xCH₃), 2.50 (2H, t, J=8 Hz, CH₂ Ph), 2.88 (1H, dd, J=2, 15 Hz, H₃),3.17 (1H, dd, J=5, 15 Hz, H₃), 3.3 (2H, m, NHCH₂), 3.89, 4.25 (each 1H,d, J=17 Hz, NCH₂), 3.99, 4.19 (each 1H, d, J=13 Hz, SOCH₂), 4.61 (1H, m,H₄), 5.02 (1H, s, OH), 6.96 (2H, s, HOPh-H), 7.25 (1H, br s, NH),7.3-7.5 (5H, m, Ph-H), Found: C, 68.9; H, 8.3; N, 5.0%; C₃₂ H₄₆ N₂ O₄ Srequires: C, 69.3; H, 8.4; N, 5.0%.

EXAMPLE 46N-6-(4-methoxyphenyl)hexyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Yellow oil, 77% yield, ¹ H NMR δ (CDCl₃) 1.3-1.6 (8H, m, 4xCH₂), 2.54(2H, t, J=15 Hz, CH₂ PhOCH₃), 2.95 (1H, dd, J=2.15 Hz, H₃), 3.23 (2H, m,NHCH₂), 3.37 (1H, dd, J=5, 15 Hz, H₃), 3.55, 3.71 (each 1H, d, J=17 Hz,NCH₂), 3.78 (3H, s, OCH₃), 3.81 (2H, s, SCH₂), 4.80 (1H, m, H₄), 6.01(1H, br s, NH), 6.82, 7.07 (each 2H, d, J=8.5 Hz, CH₃ OPh-H), 7.3 (5H,m, Ph-H).

EXAMPLE 47 (4S,SR/4S,SS)N-6-(4-methoxyphenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, 10% yield, mp 129-133.5° C., ¹ H NMR δ (CDCl₃)1.25-1.56(8H, m, CH₂ CH₂ CH₂ CH₂), 2.52(2H, t, J=7.25 Hz, CH₂ Ph-OMe),2.94 (1H, dd, J=14.75, 4.5 Hz,H_(3b)), 3.20(2H, m, NHCH₂), 3.45(1H, dd,J=14.75, 2.0 Hz,H_(3a)), 3.71, 4.23(2H, dd, J=15.5, 15.5 Hz, SOCH₂ Ph)3.78(3H, s, OCH₃), 3.88, 4.04(2H, dd, J=13.0, 12.75 Hz, N--CH₂),4.53(1H, m, H₄), 6.66(1H, s, NH), 6.78-6.83, 7.06-7.09(2H,2H, m, CH₂-Ph-OMe), 7.22-7.26, 7.36-7.40(3H,2H, m, SOCH₂ Ph). Found: B, 64.9; H,6.6; N, 6.1%; C₂₅ H₃₂ N₂ O₄ S requires: C, 65.8; H, 7.1; N, 6.1%.

EXAMPLE 48 (4R,SS/4S,SR)N-6-(4-methoxylphenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

Pale yellow solid, 29% yield, mp 85-88° C., 1H NMR δ (CDCl3)1.23-1.63(8H, m, CH₂ CH₂ CH₂ CH₂), 2.53(2H, t, J=7.25 Hz, CH₂ Ph),2.88(1H, dd, J=15.25, 2.5 Hz,H_(3a)), 3.13-3.31(3H, m, NHCH₂,H_(3b)),3.78(3H, s, OCH₃), 3.84-4.28 (4H, m NCH₂, SOCH₂ Ph), 4.61(1H, m, H₄),6.78-6.84, 7.05-7.10(2H,2H, m, CH₂ -Ph-OMe), 7.18(1H, s, CONH),7.23-7.27, 7.37-7.44(3H,2H, m, SOCH₂ Ph). Found: C, 65.5; H, 6.8; N,6.0%; C₂₅ H₃₂ N₂ O₄ S requires: C, 65.8; H, 7.1; N, 6.1%.

EXAMPLE 49N-(6-(4-chlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Pale yellow solid, 89% yield, mp 60-62° C. ¹ H NMR δ (CDCl₃) 1.3-1.6(8H, m, 4xCH₂), 2.55 (2H, t, J=7.6 Hz, PhCH₂), 2.90, 2.97 (1H, dd,J=2.4, 15.4 Hz, H₃), 3.3 (2H, m, NHCH₂), 3.33, 3.40 (1H, dd, J=5.2, 15.4Hz, H₃), 3.56, 3.71 (each 1H, d, J=16.8 Hz, NCH₂), 3.81 (2H, s, SCH₂),4.81 (1H, m, H₄), 6.05 (1H, m, NH), 7.05-7.36 (1H, m, 2xPh-H).

EXAMPLE 50 (4S,SR/4S,SS)N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

Colourless solid 17% yield, mp 178-179° C. ¹ H NMR δ (CDCl₃) 1.2-1.6(8H, m, 4sCH₂), 2.55 (2H, t, J=7.6 Hz, PhCH₂), 2.93, 2.99 (1H, dd,J=4.7, 14.8 Hz, H₃), 3.22 (2H, m, NHCH₂), 3.44, 3.49 (1H, dd, J=2.2 14.8Hz, H₃), 3.68, 4.13 (each 1H, d, J=17.4 Hz, NCH₂), 3.87, 4.05 (each 1H,d, J=13.2 Hz, SOCH₂), 4.50 (1H, m, H₄), 6.65 (1H, m, NH), 7.07-7.40 (9H,m, 2sPh-H), Found: C, 62.5; H, 6.3; N, 6.3%; C₂₄ H₂₉ ClN₂ O₃ S requires:C, 62.5; H, 6.3; N, 6.1%.

EXAMPLE 51 (4R, SS/4S,SR)N-(6-(4-chlorophenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

Colourless solid, dias. ratio 1:9, 39% yield, mp 103-104° C. ¹ H NMR(CDCl₃) δ1.3-1.6 (8H, m, 4xCH₂), 2.56 (2H, t, J=7.6 Hz, PhCH₂), 2.87,2.90 (1H, dd, J=2.5, 15.3 Hz, H₃), 3.16, 3.20 (each 1H, d, J=5.3 15.3Hz, H₃), 3.26 (2H, m, NHCH₂), 3.87, 4.25 (each 1H, d, J=17.2 Hz, NCH₂),3.98, 4.19 (each 1H, d, J=13 Hz, SOCH₂), 4.6 (1H, m, H₄), 7.07-7.41(10H, m, 2sPh-H, NH), Found: C, 62.5; H, 6.3; N, 6.2%; C₂₄ H₂₉ ClN₂ O₃ Srequires: C, 62.5; H, 6.3; N, 6.1%.

EXAMPLE 52N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Pale yellow oil, 69% yield, ¹ H NMR δ (CDCl₃) 1.30-1.60 (m, 4sCH₂), 2.57(2H, t, J=7.63 Hz, ArCH₂), 2.95 (1H, dd, J=2.4 15.4 Hz, H_(3a)) 3.24(1H, m, NHCH₂), 3.38 (1H, dd, J=5.13, 15.4 Hz, H_(3b)), 3.64 (2H, dd,J=16.8 Hz, COCH₂ N), 3.81 (2H, s, ArCH₂ S), 4.81 (1H, m, J=2.5 Hz, 5.0Hz, H₄) 6.0 (1H, m, NHC═O), 7.0-6.36 (9H, m, 9xArH).

EXAMPLE 53 (4R,SR/4S,SS)N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, dias. ratio 36:1, yield 37%, mp 158-159° C. Found: C, 58.2;H, 5.7; N, 5.7%; C₂₄ H₂₈ Cl₂ N₂ O₃ S requires: C, 58.2; H, 5.7; N, 5.7%.

EXAMPLE 54 (4R,SS/4S,SR)N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, dias. ratio 1:9, yield 22%, mp 108-109° C. Found: C, 58.2;H, 5.6; N, 5.7%; C₂₄ H₂₈ Cl₂ N₂ O₃ S requires: C, 58.2; H, 5.7; N, 5.7%.

EXAMPLE 55N-6-(3-chlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)-acetamide

Pale yellow oil, 75% yield ¹ NMR δ (CDCl₃) 1.30-1.60 (8H, m, 4×CH₂),2.55 (2H, t, J=7.63 Hz, ArCH₂), 2.95(1H, dd, J=2.5, 15.5 Hz, H_(3a)),3.24 (2H, m, J=17.5 Hz, NHCH₂), 3.38 (1H, dd, J=5.25, 15.25 Hz, H_(3b)),3.64 (2H, dd, J=16.87 Hz, COCH₂ N), 3.82 (2H, s, ArCH₂ S), 4.81 (1H, m,H₄), 6.06 (1H, m, NH), 7.0-7.36 (8H, m, 8×ArH)

EXAMPLE 56 (4R,SR/4S,SS)N-(6-(3-chorophenyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, dias. ratio 36:1, yield 18%, mp 147-148° C. Found: C,62.3;H,6.1; N,6.2%; C₂₄ H₂₉ ClN₂ O₃ S requires: C,62.5, H,6.3; N,6.1%

EXAMPLE 57 (4R,SS/4S,SR)N-(6-(3-chlorophenyl)hexyl)-4-(benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, dias. ratio 14:86, yield 49%, mp 74-75° C. Found C,62.4;H,6.2, N,6.1%; C₂₄ H₂₉ ClN₂ O₃ S requires: C,62.5; H,6.3; N,6.1%

EXAMPLE 58N-6-(4-hydroxyphenyl)hexyl-(4-benzylthio-2-oxoazetidin-1-yl)-acetamide

Yellow oil 23% yield ¹ H NMR δ (CDCl₃) 1.2-1.7 (8H, m, 4×CH₂), 2.52 (2H,t, J=15 Hz, CH₂ PhOH), 2.95 (1H, dd, J=2, 15 Hz, H₃), 3.21 (2H, m,NHCH₂), 3.37 (1H, dd, J=5, 15 Hz, H₃), 3.53, 3.72(each 1H, d, J=17 Hz,NCH₂), 3.76 (2H, s, SCH₂), 4.83 (1H, m, H₄), 5.37 (1H, s, OH), 5.97 (1H,br s, NH), 6.75, 7.02 (each 2H, d, J=8.5 Hz, HOPh--H), 7.3 (5H, m,Ph--H)

EXAMPLE 59 (4R,SR/4S,SS) and (4R,SS/4S,SR)N-6-(4-hydroxyphenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White glassy solid, dias. ratio b 1:2, 79% yield, mp 38-49° C. ¹ H NMR δ(CDCl₃) 1.25-1.58 (16H, m, 2×CH₂ CH₂ CH₂ CH₂), 2.52 (4H, t, J=7.0 Hz,2×CH₂ Ph), 2.83 (1H, dd, J=15.0, 2.0 Hz, H_(3a)), 2.90 (1H, dd, J=15.0,5.0 Hz, H_(3b)), 3.12-3.25 (5H, m, 2×NHCH₂, H_(3b)), 3.40 (1H, dd,J=15.0,2.5 Hz, H_(3a)), 3.72-4.21 (8H, m, 2×SOCH₂ Ph, 2×N--CH₂), 4.56(1H, m, H₄), 4.64 (1H, m, H₄), 6.08 (1H, s, OH), 6.17 (1H, s, OH) 6.63(1H, m, NH), 6.71-6.77, 6.97-7.04 (4H, 5H, m,2×CH₂ Ph--OH, NH),7.22-7.29,7.35-7.39 (4H, 6H, m, 2×SOCH₂ Ph). Found: C, 63.47; H,6.53;N,6.24%; C₂₄ H₃₀ N₂ O₄ S requires: C,65.13; H,6.83; N,6.33%

EXAMPLE 60N-(6-Phenylhexyl)-(4-(4-ethoxycarbonyl)benzylthio-2-oxoazetidin-1-yl)acetamide

a. 4-(4(Ethoxycarbonyl)benzylthio)azetidin-2-one

Yellow oil, 62% yield 1H NMR δ (CDCl₃) 1.40 (3H, t, J=7.13 Hz, O--CH₂CH₃), 2.85 (1H, dd, coupling indeterminate, H_(3a)), 3.31 (1H, dd,coupling indeterminate, H_(3b)) 3.88 (2H, s, S--CH₂), 4.38 (2H, q,J=7.13 Hz, O--CH₂ CH₃), 6.10 (1H, br. singlet, N--H), 7.40 (2H, d,J=8.36 Hz, Ph--H), 8.01 (2H, d, J=8.34 Hz, Ph--H)

b.N-(6-phenylhexyl)-(4-(4-ethoxycarbonyl)benzylthio-2-oxoazetidin-1-yl)acetamide

Colourless oil, 59% yield 1H NMR δ (CDCl₃) 1.23-1.71 (13H, m, CH₂ CH₂,OCH₂ CH₃), 2.56-2.62 (2H, m, Ph--CH₂), 2.93 (1H, dd, couplingindeterminate, H_(3a)), 3.18-3.27 (2H, m, NH--CH₂), 3.38 (1H, dd,J=15.37, 5.14 Hz, H_(3b)), 3.52 and 3.80 (1H each, d, J=16.64 Hz,N--CH₂), 4.37 (2H, q, J=7.13 Hz, O--CH₂ CH₃), 4.85 (1H, dd, couplingindeterminate, H₄), 6.01 (1H, br. triplet, N--H), 7.14-7.29 (5H, m,Ph--H), 7.39 (2H, d, J=8.34 Hz, Ph--H), 8.00 (2H, d, J=8.30 Hz, Ph--H).

EXAMPLE 61 (4R,SS/4S,SR)N-(6-Phenylhexyl)-4-(4-ethoxycarbonyl)benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White crystalline solid, 25% yield, mp 101-103° C. Found: C, 64.69; H,6.64; N, 5.72% C₂₇ H₃₄ N₂ O₅ S requires: C, 65.04; H, 6.87, N, 5.62%

EXAMPLE 62N-(6-phenylhexyl)-4(4-chlorobenzylthio)-2-oxoazetidin-1-ylacetamide

a. 4-(4-Chlorobenzylthio)azetidinone

Crystalline solid, 72% yield, mp 73-74° C. 1H NMR δ (CDCl₃) 2.86 (1H, m,H_(3a)), 3.32 (1H, m, H_(3b)), 3.81 (2H, s, S--CH₂), 4.68 (1H, dd,J=5.07, 2.46 Hz, H₄), 6.04 (1H, br. singlet, N--H), 7.24-7.33 (4H, m,Ph--H).

b.N-(6-phenylhex-1-yl)-4(4-chlorobenzylthio)-2-oxoazetidin-1-ylacetamide

Colourless oil, 41% yield 1H NMR δ (CDCl₃) 1.28-1.35 (4H, m, CH₂ CH₂),1.40-1.51 (2H, m, CH₂), 1.53-1.60 (2H, m, CH₂), 2.60 (2H, t, J=7.65 Hz,Ph═CH₂), 2.92 (1H, dd, J=16.37, 2.40 Hz, H_(3a)), 3.23 (2H, dt, 4 lines,NH--CH₂), 3.38 (1H, dd, J=15.36, 5.16 Hz, H_(3b)), 3.54 and 3.82 (1Heach, d, J=16.65 Hz, N--CH₂), 3.78 (2H, s, S--CH₂), 4.83 (1H, dd,J=5.15, 2.43 Hz, H₄), 7.14-7.30 (9H, m, Ph--H).

EXAMPLE 63 (4R,SR/4S,SS)N-(6-phenylhex-1-yl)-4-(4-chlorobenzylsulphinyl)-2-oxoazetidin-1-ylacetamide

White crystalline solid, mp. 155-156° C., 10% yield Found: C, 62.2; H,6.2; N, 6.1%; C₂₄ H₂₉ ClN₂ O₃ S requires: C, 62.5; H, 6.3; N, 6.1%

EXAMPLE 64 (4R,SS/4S,SR)N-(6-phenylhex-1-yl)-4(4-chlorobenzylsulphinyl)-2-oxoazetidin-1-ylacetamide

mp 92-93° C., 33% yield Found: C, 62.4; H, 6.3; N, 6.1%, C₂₄ H₂₉ ClN₂ O₃S requires: C, 62.5; H, 6.3; N, 6.1%

EXAMPLE 65 transN-(6-Phenylhexyl)-(4-benzylthio-3-methyl-2-oxoazetidin-1-yl)acetamide

Colourless oil, 65% yield 1H NMR δ (CDCl₃) 1.2-1.7 (11H, m, 4×CH₂ +CH₃),2.59 (2H, t, J=7 Hz, CH₂ Ph), 3.2 (3H, m, NHCH₂ +H₃), 3.50, 3.70 (each1H, d, J=17 Hz, NCH₂), 3.80 (2H, s, SCH₂), 4.42 (1H, d, J=2 Hz, H₄),6.04 (1H, br s, NH), 7.1-7.4 (10H, m, 2×Ph--H)

EXAMPLE 66 transN-(6-Phenylhexyl)-(4-benzylsulphinyl-3-methyl-2-oxoazetidin-1-yl)acetamide

White, semi-solid, dias. ratio 4:6, 85% yield 1H NMR δ (CDCl₃) 1.1-1.7(11H, m, 4×CH₂ +CH₃), 2.59 (2H, m, CH₂ Ph), 3.25 (2.6H, m, NHCH₂ +H₃),3.7-4.3(3.4H, m, SOCH₂ +H₄ +H₃ '), 6.65 (0.6H, br s, NH), 7.1-7.4 (10.4m, 2×Ph--H+NH'). Found: C, 67.2; H, 7.3; N, 6.0%; C₂₅ H₃₂ N₂ O₃ Srequires: C, 68.2; H, 7.3; N, 6.4%

The following compounds (Examples 67 to 69) were prepared by oxidationof the corresponding sulfides described above using the generalprocedure of Example 4.

EXAMPLE 67N-(6-phenylhexyl)-4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide

White solid, 65% yield, mp 104-105° C. Found: C, 64.7; H, 6.6; N, 6.3%,C₂₄ H₃₀ N₂ O₄ S requires: C, 65.1; H, 6.8; N, 6.3%

EXAMPLE 68N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylsulphonyl-2-oxoazetidin-1yl)acetamide

White solid, 90% yield, mp 115-116° C. Found: C, 55.2; H, 5.4; N, 5.4%;C₂₄ H₂₈ Cl₂ N₂ O₄ S.0.65H₂ O requires: C,55.1; H, 5.6, N, 5.4%

EXAMPLE 69N-(6-(3-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

White solid, 3% yield, mp 95-98° C. Found: C, 61.0; H, 6.2; N, 6.0%; C₂₄H₂₉ ClN₂ O₄ S.0.12C₆ H₁₄ requires: C, 60.9; H, 6.3; N, 5.8%

EXAMPLE 70 4-(Benzylthio)-1-(3-phenylpropyl)azetidin-2-one

A solution of 4-(benzylthio)azetidin-2-one (1.1 g, 5.5 mmol) in dry THF(10 ml) was added dropwise over 10 minutes to a suspension of NaH (0.13g, 5.6 mmol) in dry THF (5 ml) at -20° C. under a N₂ atmosphere. Asolution of 3-phenyl-1-(trifluoromethanesulfonyloxy)propane (1.5 g, 5.6mmol) in dry THF (10 ml) was added dropwise over 10 minutes at -55° C.After stirring for 1 hour, the mixture was poured into ice/water (50 g),filtered through hyflo, the THF evaporated under reduced pressure andthe residue taken up in ethyl acetate. The solution was washed withbrine (×2), dried (MgSO₄), evaporated under reduced pressure andpurified by flash chromatography on silica gel eluted with 5:1 petroleumethemethyl acetate to give the title compound as a yellow oil (1.4 g,81%). ¹ H NMR δ (CDCl₃) 2.58 (2H, m, CH₂), 2.58 (2H, t, J=15 Hz, CH₂Ph), 2.9, 3.2 (each 2H, m, H-3 & NCH₂), 3.73 (2H, s, SCH₂), 4.51 (1H, m,H-4), 7.2 (10H, m, 2×Ph--H)

EXAMPLE 71 (4R,SR/4S,SS)4-Benzylsulphinyl-1-(3-phenylpropyl)azetidin-2-one

Prepared from 4-(benzylthio)-1-(3-phenylpropyl)azetidin-2-one using thegeneral procedure of Example 2. The product was obtained as a whitesolid, dias. ratio 97:3, 19% yield, mp 93-96° C. ¹ H NMR δ (CDCl₃)1.83-1.94(2H,m,CH₂ CH₂ CH₂), 2.57-2.69(2H,m,CH₂ Ph),2.76(1H,dd,J=14.5,4.5 Hz,H_(3b)), 3.22-3.39(3H,m,N--CH₂ H_(3a)),3.83,3.98 (2H, dd, J=13.0,13.0 Hz,SOCH₂ Ph), 4.22(1H,m,H₄),7.13-7.41(10H,m,CH₂ Ph,SOCH₂ Ph). Found: C,69.5; H,6.5; N,4.5%; C₁₉ H₂₁NO₂ S requires: C,69.7; H,6.5; N,4.3%

EXAMPLE 72 (4R,SS/4S,SR)4-Benzylsulphinyl-1(3-phenylpropyl)azetidin-2-one

The mother liquors obtained from the above crystallisation werere-worked to give the title compound as a pale green oil, dias. ratio80:20, 14% yield ¹ H NMR δ (CDCl₃) 1.90-2.04(2H, m, CH₂ CH₂ CH₂),2.41(1H, dd, J=15.0, 2.4 Hz, H_(3a)), 2.59-2.64 (2H, m, CH₂ Ph), 2.84(1H, dd, J=15.0, 5.0 Hz, H_(3b)), 3.41-3.49 (2H, m, N--CH₂), 3.94-4.05(2H, dd, J=13.0, 13.0 Hz, SOCH₂ Ph), 4.23-4.26 (1H, m, H₄), 7.51-7.39(10H, m, SOCH₂ Ph, CH₂ Ph). Found: C,66.0; H,6.4; N,3.3%; C₁₉ H₂₁ NO₂ Srequires: C,69.7; H,6.5; N,4.3%

The following compounds (Examples 73-75) was prepared using the generalprocedures of Examples 70-72.

EXAMPLE 73 4-Benzylthio-1-(2-phenethyl)azetidin-2-one

Light brown oil, 60% yield 1H NMR δ (CDCl₃) 2.8-2.9 (3H, m, CH₂ Ph+H₃),3.1, 3.5 (each 1H, m, NCH₂), 3.18 (1H, dd, J=5, 15 Hz, H₃), 3.66 (2H,dd, J=14 Hz, SCH₂), 4.35 (1H, m, H₄), 7.1-7.4 (10H, m, 2×Ph--H)

EXAMPLE 74 (4R,SR/4S,SS) 4-Benzylsulphinyl-1-(2-phenethyl)azetidin-2-one

Colourless solid, 16% yield, mp 98-101° C. 1H NMR δ (CDCl₃) 2.71 (1H,dd, J=2, 15 Hz, H₃), 2.88 (2H, t, J=7 Hz, CH₂ Ph), 3.29 (1H, dd, J=2, 15Hz, H₃), 3.3 (1H, m, NCH₂), 3.7-3.9 (3H, m, NCH₂ +SOCH₂), 3.9 (1H, m,H₄), 7.1-7.4 (10H, m, Ph--H) Found: C, 68.7; H, 6.1; N, 4.5%; C₁₈ H₁₉NO₂ S requires: C, 69.0; H, 6.1; N, 4.5%

EXAMPLE 75 (4S,SS/4S,SR) 4-Benzylsulphinyl-1(2-phenethyl)azetidin-2-one

Colourless solid, 27% yield, mp 88-9° C. 1H NMR δ (CDCl₃) 2.40 (1H, dd,J=2, 15 Hz, H₃), 2.85 (1H, dd, 5, 15 Hz, H₃), 3.0 (2H, m, CH₂ CH₂ Ph),3.62, 3.76 (each 1H, m, NCH₂), 3.92, 4.03 (each 1H, d, SOCH₂), 4.16 (1H,m, H₄), 7.2-7.4 (10H, m, Ph--H) Found: C, 68.8; H, 6.2; N, 4.7%, C₁₈ H₁₉NO₂ S requires: C, 69.0; H, 6.1; N, 4.5%

EXAMPLE 76 4-(Benzylthio)-1-(4-phenylbutyl)azetidin-2-one

A solution 4-(benzylthio)azetidin-2-one (1.1 g, 5.5 mmol) in dry THF (10ml) was added dropwise over 10 minutes to a suspension of NaH (0.13 g,5.6 mmol) in dry THF (5 ml) at -20° C. under a N₂ atmosphere. A solutionof 1-iodo-4-phenylbutane (1.4 g, 5.5 mmol) in dry THF (10 ml) was addeddropwise over 10 minutes at -55° C. After stirring for 18 hours, themixture was poured onto ice/water (50 g), filtered through hyflo, theTHF evaporated under reduced pressure and the residue taken up in ethylacetate. The solution was washed with brine (×2), dried (MgSO₄),evaporated under reduced pressure to a yellow oil which was purified byflash chromatography on silica gel eluted with 5:1, 3:1 then 1:1petroleun ether/ethyl acetate to give the product as a yellow oil (0.25g, 14%). ¹ H NMR δ (CDCl₃) 1.5 (4H, m, 2×CH₂), 2.6 (2H, m, CH₂ Ph),2.85, 3.2 (each 2H, m, H-3 & NCH₂), 3.73 (2H, s, SCH₂), 4.54 (1H, m,H-4), 7.2 (10H, m, 2×Ph--H)

EXAMPLE 77 (4R,SS/4S,SR)4-Benzylsulphinyl-1-(4-phenylbutyl)azetidin-2-one

Prepared from 4-(benzylthio)-1(4-phenylbutyl)azetidin-2-one using thegeneral procedure of Example 30. The product was obtained as a yellowoil following flash chromatography, 76% yield ¹ H NMR δ (CDCl₃)1.61-1.66(8H,m,2×CH₂ CH₂ CH₂ CH₂), 2.47(1H,dd,J=15.0, 1.50 Hz,H_(3a)),2.60(4H,m,2×CH₂ Ph), 2.83(1H,dd,J=14.5,4.5 Hz,H_(3b)), 2.93(1H,dd,J=15.0,5.0 Hz,H_(3b)), 3.29-3.50(5H,m,2×N--CH₂,H_(3a)),3.98,4.06(2H,dd,J=13.25, 13.25 Hz,SOCH₂ Ph), 3.83,3.93(2H,dd,J=6.25,6.25Hz,SOCH₂ Ph), 4.28(1H,m,H₄), 4.31(1H,m,H₄), 7.12-7.39(20H,m,2×CH₂Ph,2×SOCH₂ Ph). Found: C,59.2; H,6.9; N,4.5%; C₂₀ H₂₃ NO₂ S requires:C,70.2; H,6.8; N,4.1%

EXAMPLE 78 p-Methoxybenzyl [(3S,4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]acetate

a. p-Methoxybenzyl [(3S,4R)-4-acetylthio-3-bromo-2-oxoazetidin-1-yl]acetate

Ozonised oxygen was bubbled through a solution of p-methoxybenzyl 2[(3S,4R)-4-acetylthio-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(Osborne N. F. et al., J. Chem. Soc. Perkin Trans. 1, 1994, 179) (20.16g, 0.0456 mol) in ethyl acetate (400 ml) at -65° to -70° C. until apermanent blue solution was obtained. Excess ozone was removed by thepassage of oxygen, then trimethyl phosphite (53.8 ml, 0.456 mol) wasadded dropwise. After 15 min. the solution was allowed to warm to roomtemperature, then stood for 16 hr. The solvents were evaporated and theresidue reevaporated twice from toluene, then dissolved in ethyl acetate(300 ml) and stirred vigorously for 1.5 hr. with a solution ofp-toluenesulphonic acid (2 g) in water (100 mol). After dilution withwater the organic layer was separated and the aqueous layer furtherextracted with ethyl acetate. The combined extracts were washedsuccessively with saturated aq. sodium hydrogen carbonate and brine,then dried ((MgSO₄) and evaporated. Purification by flash chromatography(silica, ethyl acetate-pet. ether) gave the product as a light brownoil, yield 10.6 g (58%).

b. Silver(3S,4R)-3-bromo-1-(p-methoxybenzyloxycarbonylmethyl)-2-oxoazetidine-4-thiolate

A solution of p-methoxybenzyl [(3S,4R)-4-acetylthio-3-bromo-2-oxoazetidin-1-yl]acetate (4.13 g, 0.01 mol)in methanol (90 ml) was added with stirring in subdued light to asolution of silver nitrate (2.27 g, 0.0133 mol) in methanol (90 ml).Triethylamine (1.87 ml, 0.0133 mol) was then added with ice cooling, andstirring continued for 1 hr. at 5-10° C. followed by 30 min. at roomtemperature. The mixture was re-cooled (ice bath) and the precipitatedsolid filtered and washed twice with ice cold methanol then hexane togive the title compound, yield, 4.6 g (96%).

c. p-Methoxybenzyl [(3S,4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]acetate

A solution of silver(3S,4R)-3-bromo-1-(p-methoxybenzyloxycarbonylmethyl)-2-oxoazetidine-4-thiolate(4.6 g, 0.0099 mol) in acetonitrile (100 ml) was treated with benzylbromide (1.76 ml, 0.015 mol) under nitrogen and the mixture stirred insubdued light for 48 hr. The solvent was evaporated, the residue treatedwith dichloromethane and the precipitated salts filtered off. Thefiltrate was evaporated and the residue purified by flash chromatography(silica, ethyl acetate-pet. ether) to give the title compound as an oil,yield 3.37 g (76%). 1H NMR δ (CDCl₃), 3.39, 4.02 (each 1H, d, J=18.1 Hz,NCH₂), 3.76 (2H, s, SCH₂), 3.81 (3H, s, OCH₃), 4.61, 4.91 (each 1H, d,J=1.6 Hz, H₃ +H₄), 5.08 (2H, m, OCH₂), 6.89 (2H, m, 3.5-(4-CH₃ OPh)-H),7.22-7.33 (7H, m, Ph--H+2.6-(4-CH₃ OPh)--H).

EXAMPLE 79(3S,4R)-N-(6-phenylhexyl)-1-(4-benzylthio-3-bromo-2-oxoazetidin-1-yl)acetamide

a) p-Methoxybenzyl 2[(3S,4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]-3-methybut-2-enoate

A solution of the silver salt of p-methoxybenzyl 2-[(3S,4R)-4-mercapto-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (10 g,20 mmol) in dry acetonitrile (100 ml) was treated with benzyl bromide (4g, 24 mmol) and the resulting mixture refluxed for 30 mins. the reactionwas cooled to room temperature, filtered, evaporated to dryness and theresidue purified by flash chromatography using 1:1 ether:pentane as theeluting solvent. Evaporation of the appropriate fractions gave theproduct as a white solid (5.8 g, 59%), mp 70-72° C. ¹ H NMR δ(CDCl₃)1.93 (3H, s, CH₃), 2.23 (3H, s, CH₃), 3.66 (1H, dd, J=2.9, 17.5Hz, SCH₂), 3.79 (3H, s, OCH₃), 4.52 (1H, d, J=1.8 Hz, H₃), 4.95 (1H, d,J=1.9 Hz, H₄), 5.08 (2H, q, J=12.0 Hz, CO₂ CH₂), 6.84-6.90 (2H, m,2.6Ph--H), 7.13-7.31 (7H, m, 3,5Ph--H,Ph--H).

b) (3S, 4R)-4-Benzylthio-3-bromoazetidin-2-one

Ozonised oxygen was bubbled through a solution of p-methoxybenzyl2-[(3S,4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (2 g,4 mmol) in dichloromethane (40 ml) at -78° C. and the reaction monitoredby infra-red spectroscopy. When the band at 1780 cm⁻¹ had disappeared,methanol (4 ml) together with a trace of sodium methoxide and dimethylsulfide (1 ml) was added and stirring continued at room temperature for16 h. The reaction was evaporated and the residue purified by flashchromatography using 1:1 ether:pentane as the eluting solvent.Evaporation of the appropriate fractions gave the product as acolourless oil (0.7 g, 64%). ¹ H NMR δ (CDCl₃) 3.87 (2H, s, SCH₂), 4.52(1H, m, H₄), 4.69 (1H, d, H₃) 5.85 (1H, bs, NH), 7.18-7.39 (5H, m,Ph--H).

c) N-(6-Phenylhexyl)[(3S,4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]acetamide

A solution of (3S, 4R)-4-benzylthio-3-bromoazetidin-2-one (0.7 g, 2.6mmol) in dry THF (25 ml) was treated withN-(6-phenylhexyl)bromoacetamide (0.8 g, 2.6 mmol), powdered potassiumhydroxide (0.2 g 3 mmol) and tetrabutylammonium hydroxide (0.1 g, 0.3mmol). The mixture was stirred at room temperature for 4 h andpartitioned between ether and brine. The organic layer was separated,dried (MgSO₄) and evaporated. The residue was purified by flashchromatography using 3:1 ether:pentane as the eluting solvent.Evaporation of the appropriate fractions gave the title compound as anoil (0.63 g, 53%). ¹ H NMR δ (CDCl₃) 1.21-1.66 (8H, m, (CH₂)₄), 2.59(2H, t, J=7.4 Hz, CH₂), 3.48,3.82 (each 1H, d, J=16 Hz, NCH₂), 3.21 (2H,h, J=6.00 Hz, CH₂), 3.37 (1H, dd, J=5.15 Hz, H_(3b)), 3.83 (2H, s,SCH₂), 4.59 (1H, d, J=1.6 Hz, H₄), 4.89 (1H, d, J=1.6 Hz, H₃), 6.04 (1H,bt, NH), 7.14-7.36 (10H, m, Ph--H).

Examples 80 and 81 were prepared from(3S,4R)-N-(6-phenylhexyl)-4-benzylthio-3-bromo-2-oxoazetidin-1-ylacetamide by the method described in Example 2 and 3

EXAMPLE 80(3S,4R,SR)-N-(6-phenylhexyl)-4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-ylacetamide

White crystals m.p. 115-117° C., 17.5% yield Found: C, 57.9; H, 6.0; N,6.0%; C₂₄ H₂₉ N₂ O₃ S requires: C, 57.0; H, 5.8; N, 5.5%

EXAMPLE 81(3S,4R,SS)-N-(6-phenylhexyl)-4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-ylacetamide

Colourless solid, mp. 105-107° C., 15% yield Found: C, 57.5H, 6.0; N,5.5%, C₂₄ H₂₉ N₂ O₃ S requires: C, 57.0; H, 5.8, N, 5.5%

EXAMPLE 82(4R,SS/4R,SR)-N-(6-phenylhexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide

Treatment of(3S,4R,SS)-N-(6-phenylhexyl)-4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-ylacetamidein either of the procedures below gave(4R,SS/4R,SR)-N-(6-phenylhexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide as a mixture whose NMR spectra were identical to a mixture ofExamples 30 and 31.

a. To a stirring suspension of activated zinc powder (51.7 mg, 0.79mmol) in dichloromethane (1.2 ml) and acetic acid (0.4 ml) at 5-10° C.was addedN-(6-phenylhexyl)[(4R)-4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-yl]acetamide(0.2 g, 0.4 mmol). After 1 hr, the mixture was diluted withdichloromethane-water, and the organic layer washed with saturated aq.NaHCO₃, dried (MgSO₄) and evaporated to an oil. Crystallisation fromethyl acetate gave the product as a mixture of diastereoisomers4R,SS:4R,SR in the ratio 6:1, yield 48 mg (28%), m.p. 120-1° C. Thefiltrate was evaporated and the residue treated with ether to give asecond crop as a 3:1 mixture of diastereoisomers, yield 50 mg (30%),m.p. 108-11° C.

b. A suspension ofN-(6-phenylhexyl)[(4R)-4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-yl]acetamide(0.3 g, 0.59 mmol) and 10% palladium on charcoal (50 mg) in ethanol wastreated with a solution of sodium hydrogen carbonate (50 mg, 0.59 mmol)in a small amount of water and hydrogenated at 50 psi for 2 hr. Thecatalyst was filtered off through hyflo and the filtrate evaporated toan oil, which was treated with water and extracted three times withdichloromethane. The combined extracts were dried (MgSO₄) and evaporatedto an oil which crystallised from either to give the product as amixture of diastereoisomers 4R,SS:4R,SR in the ratio 3:1, yield 0.17 g(68%), m.p. 110-13° C.

EXAMPLE 83(3S,4R)-N-(6-phenylhexyl)-1-(4-benzylthio-3-bromo-2-oxoazetidin-1-yl)acetamide

a) ((3S, 4R)-4-Benzylthio-3-bromo-2-oxoazetidin-1-yl)acetic acid

To a solution of p-methoxybenzyl [(3S,4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]acetate (3.03 g, 0.0067 mol)in methanol (50 ml) at -5 to -10° C. a 1M solution of potassiumhydroxide (7.4 ml) was added dropwise with stirring. After 2 h, themethanol was evaporated off and the residue diluted with water,extracted twice with ether, and the aq. layer acidified with ice coolingto pH 3 (2M HCl). The oil which precipitated soon crystallised and wasfiltered, washed and dried to give the title compound, yield 0.9 g(41%), m.p. 138-40° C.

b)(3S,4R)-N-(6-phenylhexyl)-1-(4-benzylthio-3-bromo-2-oxoazetidin-1-yl)-acetamide

Treatment of the above acetic acid with 6-phenylhexylamine as describedin Example 29 gave the title compound, with identical spectra to Example79.

EXAMPLE 84(4R,SS)-N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

see examples 154 to 157

EXAMPLE 85N-[6-(4-Fluorophenyl)hexyl]-4-(4-methoxybenzylthio)-2-oxoazetidin-1-ylacetamide

a. N-[6-(4-Fluorophenyl)hexyl]-1-bromoacetamide

A cooled solution of 6-(4-fluorophenyl)hexylamine (2.0 g) and Hunig'sbase (1.33 g) in dry dichloromethane (25 ml) was treated withbromoacetylbromide (2.07 g) in dichloromethane (10 ml) at 0-5° C. Afterworkup and chromatography N-[6-(4-Fluorophenyl)hexyl]-1-bromoacetamidewas obtained as a colourless solid, 2.71 g, m.p.50-51° C.

b.N-[6-(4-Fluorophenyl)hexyl]-4-(4-methoxybenzylthio)-2-oxoazetidin-1-ylacetamide

4-(4-Methoxybenzylthio)-2-oxoazetidinone (2.65 g) was treated with theabove bromoacetamide (4 g) in dry THF in the presence of potassiumhydroxide (0.7 g) and tetra-n-butylammonium bromide (0.4 g) to giveN-[6-(4-fluorophenyl)hexyl]-4-(4-methoxybenzylthio)-2-oxoazetidin-1-ylacetamide(3.8 g, 65% yield) as colourless crystals, m.p. 53-5° C., afterchromatography. ¹ H NMR δ (CDCl₃) 1.33 (4H, m), 1.58 (4H, m), 2.56 (2H,t), 2.94 (1H, dd), 3.24 (2H, m), 3.37 (1H, dd), 3.61 (1H, d), 3.75 (1H,d), 3.77 (2H, s), 3.79 (3H, s), 4.79 (1H, dd), 6.09 (1H, m), 6.82-7.26(8H, m).

EXAMPLE 86N-(6-(2,4-Difluorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Sequential treatment of (4-benzylthio-2-oxoazetidin-1-yl)acetic acidwith 1-cyclohexyl-3-(2-morpholinethyl)carbodiimidemetho-p-toluenesulfonate and 6-(2,4-difluorophenyl)hexylamine indimethyl formamide by the method described for Example 29 gave the titlecompound as a colourless solid, m.p. 65-66° C., in 73% yield ¹ H NMR δ(CDCl₃) 1.3-1.36 (4H, m, 4×CH₂), 1.50-1.60 (4H, m, 4×CH₂), 2.58 (2H, t,J=7.6 Hz, PhCH₂), 2.93, 2.97 (1H, dd, J=2.4, 15.6 Hz, H₃), 3.23 (2H, m,NHCH₂), 3.35, 3.39 (1H, dd, J=5.2, 15.2 Hz, H₃), 3.57, 3.71 (each 1H, d,J=16.4 Hz, NCH₂), 3.81 (2H, s, SOCH₂), 4.80 (1H, m, H₄), 6.02 (1H, m,HH), 6.76-7.33 (8H, m, 2Ph--H); ν_(c=o) 1774 cm⁻¹ Found: C, 64.5; H,6.3; N, 6.5%, C₂₄ H₂₈ F₂ N₂ O₂ S requires: C, 64.6; H, 6.3; N, 6.3%

The following amides, Examples 87-96 were prepared by one of the methodsdescribed in Examples 29, 85 or 86.

EXAMPLE 87N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxybenzylthio)-2-oxoazetidin-1-ylacetamide

White crystals, m.p.65-6° C., 89% yield; Found: C, 63.1; H, 6.5; N,6.1%; C₂₅ H₃₁ ClN₂ O₃ S requires: C, 63.2; H, 6.6; N, 5.9%

EXAMPLE 88N-(6-(3,4-Difluorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Colourless solid, m.p. 53-54° C., 77% yield; ¹ H NMR δ (CDCl₃) 1.3-1.39(4H, m, 4×CH₂), 1.44-1.60 (4H, m, 4×CH₂), 2.55 (2H, t, J=7.6 Hz, PhCH₂),2.91, 2.97 (1H, dd, J=2.4, 15.4 Hz, H₃), 3.23 (2H, m, NHCH₂), 3.34, 3.40(1H, dd, J=5.2, 15.4 Hz, H₃), 3.56, 3.71 (each 1H, d, J=16.8 Hz, NCH₂),3.81 (2H, s, SOCH₂), 4.80 (1H, m, H₄), 6.09 (1H, m, NH), 6.82-7.33 (8H,m 2Ph--H); ν_(c=o) 1776 cm⁻¹ Found: C, 64.2; H, 6.3; N, 6.2%; C₂₄ H₂₈ F₂N₂ O₂ S requires: C, 64.6H, 6.3; N, 6.3%

EXAMPLE 89 N-(7-phenylhept-1-yl)-4-benzylthio-2-oxoazetidin-1-ylacetamide

White crystalline solid, m.p. 63-65° C., 96% yield; ¹ H NMR δ (CDCl₃)1.25-1.63 (10H, m), 2.59 (2H, t), 2.93 (1H, dd), 3.22 (2H, dt), 3.36(1H, dd), 3.50, 3.71 (each 1H, d), 3.81 (2H, s), 4.81(1H, dd), 6.05 (1H,br. singlet), 7.13-7.36 (10H, m).

EXAMPLE 90N-(6-[4-chlorophenyl]hex-1-yl)-(4-methooxycarbonylbenzylthio)-2-oxoazetidin-1-ylacetamide

White crystals, m.p. 87-88° C., 88% yield; Found: C, 62.0; H, 6.2; N,6.0%; C₂₆ H₃₁ ClN₂ O₄ S requires: C, 62.1; H, 6.2; N, 5.6%

EXAMPLE 91 N-(5-phenylpentyl)-4-benzylthio-2-oxo-azetidinyl-1-ylacetamide

Colourless oil, 70% yield; ¹ H NMR δ (CDCl₃)1.38-1.65(6H, m,(CH₂)₃), 2.6(2H, t, J=7.75 Hz), 2.89-2.96(1H, dd, J=2.5,15 Hz H_(3a)), 3.32 (2H, q,J=6.68 Hz, NHCH₂) 3.34 (1H, dd, J=5, 15 Hz, H_(3b)), 3.59,3.70 (each 1H,d, J=17.00 Hz, NCH₂), 3.8 (2H, s, SCH₂), 4.80 (1H, m, H₄), 6.07 (1H, bs,NH),7.14-7.33 (10H, m, Ph--H).

EXAMPLE 92N-(6-(4-Bromophenyl)hexyl)-4-benzylthio-2-oxoazetidin-1-ylacetamide

Colourless solid, m.p. 73-5° C., 91% yield; ¹ H NMR δ (CDCl₃) 1.2-1.7(8H, m, 4×CH₂), 2.54 (2H, t, J=8 Hz, CH₂ Ar), 2.94 (1H, dd, J=2, 15 Hz,H₃), 3.23 (2H, m, NCH₂), 3.37 (1H, dd, J=5, 15 Hz, H₃), 3.56, 3.71 (each1H, d, J=17 Hz, NCH₂), 3.81 (2H, s, SCH₂), 4.80 (1H, m, H₄), 6.06 (1H,br s, NH), 7.0-7.4 (9H, m, Ph--H+BrPh--H)

EXAMPLE 93N-(6-(4-Fluorophenyl)hexyl)-4-benzylthio-2-oxoazetidin-1-ylacetamide

Colourless oil, 97% yield; ¹ H NMR δ (CDCl₃) 1.2-1.7 (8H, m, 4×CH₂),2.56 (2H, t, J=8 Hz, CH₂ Ar), 2.94 (1H, dd, J=2, 15 Hz, H₃), 3.23 (2H,m, NCH₂), 3.37 (1H, dd, J=5, 15 Hz, H₃), 3.56, 3.72 (each 1H, d, J=17Hz, NCH₂), 3.81 (2H, s, SCH₂), 4.81 (1H, m, H₄), 6.07 (1H, br s, NH),6.9-7.4 (9H, m, Ph--H+FPh-H)

EXAMPLE 94 N-[5-(4-chlorophenyl)pentyl]-4-benzylthio-2-oxo-azetidin-1-ylacetamide

Colourless oil, 63.4% yield ¹ H NMR δ (CDCl₃) 1.36-1.62 (6H, m, 3×CH₂),2.56 (2H, t, J=7.58 Hz, ArCH₂), 2.94 (1H, dd, 2.44 Hz, 15.38 Hz,H3_(a)), 3.23(2H, m, NHCH₂), 3.36 (1H, dd, J=5.17 Hz, 15.38 Hz, H_(3b)),3.62&3.55 (1H each, J=16.8 Hz, NCH₂), 3.80 (2H, , SCH₂ Ph), 4.78 (1H,dd, J=2.46 Hz, 5.16 Hz, H₄), 6.05 (1H, m, NHC═O), 7.06-7.33 (9H, m,9×ArH)

EXAMPLE 95 N-[6-(2-Chlorophenyl)hexyl]-4-benzylthio-2-oxo-azetidin-1ylacetamide

Colourless oil, 84% yield ¹ H NMR δ (CDCl₃) 1.34-1.67 (8H, m, 4×CH₂),2.71 (2H, t, J=7.7 Hz, ArCH₂), 2.94 (1H, dd, 2.5 Hz, 15.4 Hz, H_(3a)),3.21 (2H, m, NHCH₂), 3.37 (1H, dd, J=5.2 Hz, 15.4 Hz, H_(3b)), 3.55,3.72 (1H each, J=16.75 Hz, NC ₂), 3.81 (2H, s, SCH₂ Ph), 4.82 (1H, dd,J=2.5 Hz, 5.2 Hz, H₄), 6.09 (1H, m, NHC═O), 7.10-7.33 (9H, m, 9×ArH)

EXAMPLE 96N-(6-[4-chlorophenyl]hex-1-yl)-(4-allyloxycarbonylbenzylthio)-2-oxoazetidin-1-yl-acetamide

Pale orange oil, 36% yield 1H NMR δ (CDCl₃) 1.25-1.59 (10H, m), 2.55(2H, m), 2.94 (1H, dd), 3.38 (1H, dd), 3.53 and 3.83 (1H each, d), 3.96(2H, s), 4.83 (2H, m), 5.27-5.45 (2H, m), 5.92-5.09 (2H, m) 7.07 (1H,d), 7.22 (1H, d), 7.39 (1H, d), 8.02 (1H, d).

EXAMPLE 97N-[6-(4-methylphenyl)-hexyl]-[4-benzylsulphinyl-2-oxo-azetidin-1-yl]-acetamide

Colourless solid, m.p. ⊖-4° C., 79% yield ¹ H NMR δ (CDCl₃) 1.30-1.60(8H, m, 4×CH₂), 2.31 (3H, s, ArCH₃), 2.55 (2H, t, J=7.61 Hz, ArCH₂),2.94(1H, dd, J=2.5, 15.4 Hz, H_(3a)), 3.23 (2H, m, J=13.75 Hz, NHCH₂),3.38(1H, dd, J=5.17, 15.37 Hz, H_(3b)), 3.63 (2H, dd, J=16.75 Hz, COCH₂N). 3.81 (2H, s, ArCH₂ S), 4.80 (1H, m, J=5.14, 2.47 Hz, H₄), 6.00 (1H,m, NH), 7.03-7.36 (9H, m, 9×ArH)

Examples 98 and 99 were prepared by the general procedure of Example 86substituting the phenylhexanols for the amine.

EXAMPLE 98 6-Phenylhexyl (4-benzylthio-2-oxo-azetidin-1-yl)acetate

Colourless oil, 33% yield, ¹ H NMR δ (CDCl₃) 1.35-1.60 (8H, m, 4×CH₂),2.61 (2H, t, J=7.64 Hz, ArCH2), 3.01 (1H, dd, 2.12 Hz, 5.37 Hz, H_(3a))3.39 (1H, dd, J=5.1 Hz, 15.26 Hz, H_(3b)), 3.25, 4.00 (1H each, J=18.09Hz, NCH₂), 3.77 (2H, s, SCH₂ Ph), 4.05 (2H, m, OCH₂), 4.93 (1H, dd,J=2.37 Hz, 5.07 Hz, H₄), 7.15-7.31 (10H, m, 10×ArH)

EXAMPLE 996-(4-Chlorophenyl)hexyl-[4-benzylthio-2-oxo-azetidin-1yl]acetate

Colourless oil, 27% yield, ¹ H NMR δ (CDCl₃) 1.31-1.68 (8H, m, 4×CH₂),2.57 (2h, t, J=7.61 Hz, ArCH₂), 2.97 (1H, dd, 2.17 Hz, 15.17 Hz, H3a,3.40 (1H, dd, J=5.1 Hz, 15.25 Hz, H_(3b)), 3.25, 4.00 (1H each, J=18.10Hz, NCH₂), 3.77 (2H, s, SCH₂ Ph), 4.10 (2H, m, OCH₂), 4.93 (1H,dd,J=2.37 Hz, 5.10 Hz, H₄), 7.10-7.35 (9H, m, 9×ArH)

EXAMPLE 100 1-(9-Phenylnonyl)-4-benzylthio-2-oxoazetidine

Treatment of 4-benzylthio-2-oxo-azetidine (1.35 g) in THF with NaH (0.18g) followed by 9-phenylnonyltriflate (2.8 g) gave the title compound asa colourless oil, 1.9 g, 68% yield. ¹ H NMR δ (CDCl₃) 1.2-1.7 (14H, m,7×CH₂), 2.60 (2H, t, J=8 Hz, CH₂ Ar), 2.8, 3.2 (each 2H, m, H₃ +NCH₂),3.76 (2H, s, SCH₂), 4.59 (1H, m, H₄), 7.15-7.35 (10H, m, Ph--H)

The following sulfoxides (Examples 101-130) were prepared by treatmentof the corresponding sulfides with mCPBA as described for Examples 2 and3. When described as Diastereoisomer 1 the compounds are predominantly4R,SR/4S,SS, whereas Diastereoisomer 2 is predominantly 4R,SS/4S,SR.

EXAMPLE 101N-[6-(4-Fluorophenyl)hexyl]-4-(4-methoxybenzylsulphinyl)-2-oxoazetidin-1-ylacetamide(Diastereoisomer 1)

Colourless crystals, m.p. 147-9° C., 19% yield Found: C, 63.2; H, 6.5;N, 6.0%, C₂₅ H₃₁ FN₂ O₄ S requires: C, 63.3; H, 6.6; N, 5.9%

EXAMPLE 102N-[6-(4-Fluorophenyl)hexyl]-4-(4-methoxybenzylsulphinyl)-2-oxoazetidin-1-ylacetamide(Diastereoisomer 2)

Colourless crystals, m.p. 97-9° C., 48% yield Found: C, 63.1; H, 6.4; N,5.8%; C₂₅ H₃₁ FN₂ O₄ S requires: C, 63.3; H, 6.6; N, 5.9%

EXAMPLE 103N-(6-(2,4-Difluorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 1)

Colourless solid, m.p. 153° C., 19% yield; ¹ H NMR δ (CDCl₃) 1.3-1.36(4H, m, 4×CH₂), 1.50-1.60 (4H, m, 4×CH₂), 2.57 (2H, t, J=7.6 Hz, PhCH₂),2.94, 2.98 (1H, dd, J=4.8, 14.8 Hz, H₃), 3.23 (2H, m, NHCH₂), 3.44, 3.48(1H, dd, J=2.0, 14.8 Hz, H₃), 3.70, 4.12 (each 1H, d, J=17.2 Hz, NCH₂),3.89, 4.05 (each 1H, d, J=13.2 Hz, SOCH₂), 4.51 (1H, m, H₄), 6.64 (1H,m, NH), 6.72-7.41 (8H, m, 2Ph--H); ν_(c=o) 1791 cm⁻¹ Found: C, 62.3; H,6.1; N, 6.1%; C₂₄ H₂₈ F₂ N₂ O₃ S requires: C, 62.3; H, 6.1; N, 6.1%

EXAMPLE 104N-(6-(2,4-Difluorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

Colourless solid, m.p. 114-116° C., 46% yield ¹ H NMR δ (CDCl₃) 1.3-1.36(4H, m, 4×CH₂), 1.50-1.60 (4H, m, 4×CH₂), 2.58 (2H, t, J=7.6 Hz, PhCH₂),2.87, 2.90 (1H, dd, J=2.4, 15.2 Hz, H₃), 3.16, 3.19 (1H, dd, J=5.6, 15.2Hz, H₃), 3.27 (2H, m, NHCH₂), 3.88, 4.25 (each 1H, d, J=17.2 Hz, NCH₂),3.99, 4.20 (each 1H, d, J=13.2 Hz, SOCH₂), 4.60 (1H₄), 6.72-7.41 (9H, m,2Ph--H, NH) ν_(c=o) 1793 cm⁻¹ Found: C, 62.3; H, 6.1; N, 6.2%; C₂₄ H₂₈F₂ N₂ O₃ S requires: C, 62.3; H, 6.1; N, 6.1%

EXAMPLE 105N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxybenzylsulphinyl)-2-oxoazetidin-1-ylacetamide(Diastereoisomer 1)

Colourless crystals, m.p. 147-9° C., 32% yield Found: C, 61.0; H, 6.2;N, 6.0%; C₂₅ H₃₁ ClN₂ O₄ S requires: C, 61.2; H, 6.4; N, 5.7%

EXAMPLE 106N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxybenzylsulphinyl)-2-oxoazetidin-1-ylacetamide(Diastereoisomer 2)

Colourless crystals, m.p. 102-3° C., 31% yield Found: C, 60.6; H, 6.2,N, 5.8%; C₂₅ H₃₁ ClN₂ O₄ S.0.3H₂ O requires: C, 60.5H, 6.4; N, 5.6%

EXAMPLE 107N-(6-(3,4-Difluorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 1)

Colourless solid, m.p. 171° C., 20% yield ¹ H NMR δ (CDCl₃) 1.3-1.36(4H, m, 4×CH₂), 1.50-1.60 (4H, m, 4×CH₂), 2.54 (2H, t, J=7.6 Hz, PhCH₂),2.93, 2.99 (1h, dd, J=4.7, 14.9 Hz, H₃), 3.22 (2H, m, NHCH₂), 3.43, 3.48(1H, dd, J=2.2, 14.9 Hz, H₃), 3.70, 4.12 (each 1H, d, J=17.4 Hz, NCH₂),3.89, 4.05 (each 1H, d, J=13.1 Hz, SOCH₂), 4.51 (1H, m, H₄), 6.72 (1H,m, NH), 6.87-7.41 (8H, m, 2Ph--H); ν_(c=o) 1791 cm⁻¹ Found: C, 62.3; H,6.1; N, 6.2%; C₂₄ H₂₈ F₂ N₂ O₃ S requires: C, 62.3; H, 6.1; N, 6.1%

EXAMPLE 108N-(6-{3,4-Difluorophenyl}hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2)

Colourless solid, m.p. 115-116° C., 58% yield ¹ H NMR δ (CDCl₃) 1.3-1.36(4H, m, 2×CH₂), 1.50-1.60 (4H, m, 2×CH₂), 2.54 (2H, t, J=7.6 Hz, PhCH₂),2.87, 2.92 (1H, dd, J=2.5, 15.3 Hz, H₃), 3.16, 3.19 (1H, dd, J=5.4, 15.3Hz, H₃), 3.27 (2H, m, NHCH₂), 3.88, 4.25 (each 1H, d, J=17.2 Hz, NCH₂),3.98, 4.21 (each 1H, d, J=13.0 Hz, SOCH₂), 4.60 (1H, m, H₄), 6.85-7.41(9H, m, 2Ph--H, NH) ν_(c=o) 1793 cm⁻¹ Found: C, 62.4; H, 6.1; N, 6.1%;C₂₄ H₂₈ F₂ N₂ O₃ S requires: C, 62.3; H, 6.1; N, 6.1%

EXAMPLE 109 N-(7-phenylhept-1-yl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide (Diastereoisomer 1)

Colourless crystalline solid, m.p. 143-144° C., 27% yield Found: C,67.7; H, 7.1; N, 6.3%; C₂₅ H₃₂ N₂ O₃ S 0.1H₂ O requires: C, 67.9; H,7.3; N, 6.3%

EXAMPLE 110 N-(7-phenylhept-1-yl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide (Diastereoisomer 2)

Colourless crystalline solid, m.p. 133-34° C., 40% yield Found: C, 67.8;H, 7.1; N, 6.3%; C₂₅ H₃₂ N₂ O₃ S requires: C, 68.2; H, 7.3; N, 6.4%

EXAMPLE 111N-(6-[4-chlorophenyl]hex-1-yl)-4-methoxycarbonylbenzylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereoisomer 1)

Form white crystals, m.p. 188-9° C., 17% yield Found: C, 60.1; H, 6.0;N, 5.5%; C₂₆ H₃₁ ClN₂ O₅ S requires: C, 60.2; H, 6.0; N, 5.4%

EXAMPLE 112N-(6-[4-chlorophenyl]hex-1-yl)-(4-methoxycarbonylbenzylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereoisomer 2)

Form white crystals, m.p. 140-41° C., 51% yield Found: C, 60.1; H, 6.0;N, 5.4%; C₂₆ h₃₁ ClN₂ O₅ S requires: C, 60.2; H, 6.0; N, 5.4%

EXAMPLE 113N-(6-phenylhex-1-yl)-(4-ethoxycarbonylbenzylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereoisomer 1)

Colourless crystals, m.p. 177-178° C., 8.4% yield Found: C, 64.3H, 6.7;N, 5.7%; C₂₇ H₃₄ N₂ O₅ S 0.3 H₂ O requires: C, 64.3; H, 6.9; N, 5.6%

EXAMPLE 114N-(6-[4-chlorophenyl]hex-1-yl)-(4-allyloxycarbonyl-benzylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereoisomer 2)

White crystalline solid, m.p. 100-112° C., 30% yield Found: C, 61.7; H,6.1; N, 5.1% C₂₈ H₃₃ ClN₂ O₅ S requires C, 61.7; H, 6.1; N, 5.1%

EXAMPLE 115 N-(5-phenylpentyl)-4-benzylsulphinyl-2-oxo-azetidinyl-1-ylacetamide

Colourless solid, m.p. 140-142° C., 6.5% yield ν_(c=o) 1790,1690 cm⁻¹Found: C, 66.6; H, 6.7; N, 6.8%; C₂₃ H₂₈ N₂ O₃ requires: C, 67.0; H,6.8; N, 6.8%

EXAMPLE 116N-(5-(4-Chlorophenyl)pentyl)-4-benzylsulphinyl-2-oxo-azetidin-1ylacetamide (Diastereoisomer 1)

Form, White crystals, m.p. 146-47° C., 31.5% yield Found: C, 61.94; H,6.1; N, 6.8%; C₂₃ H₂₇ ClN₂ O₃ S requires: C, 61.8; H, 6.1; N, 6.3%

EXAMPLE 117N-(5-(4-Chlorophenyl)pentyl)-4-benzylsulphinyl-2-oxo-azetidin-1ylacetamide (Diastereoisomer 2)

Colourless crystals, m.p. 117-19° C., 53.8% yield Found: C, 61.7; H,5.9; N, 6.4%, C₂₃ H₂₇ ClN₂ O₃ S requires: C, 61.8; H, 6.1; N, 6.3%

EXAMPLE 118N-[5-(2-Chlorophenyl)hexyl]-4-benzylsulphinyl-2-oxo-azetidin-1ylacetamide (Diastereoisomer 1)

Colourless crystals, m.p. 96-8° C., 35.2% yield Found: C, 61.82; H,6.18;N,6.14%; C₂₄ H₂₉ ClN₂ O₃ S.0.3H₂ O requires: C,61.81; H,6.40; N,6.01%

EXAMPLE 119N-[5-(2-Chlorophenyl)hexyl]-4-benzylsulphinyl-2-oxo-azetidin-1ylacetamide

Colourless crystals, m.p.86-8° C., 57% yield Found: C, 62.6; H, 6.2; N,6.1%, C₂₄ H₂₉ ClN₂ O₃ S requires: C,62.5; H,6.3; N,6.1%

EXAMPLE 120N-(6-(4-Bromophenyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide(Diastereoisomer 1)

Colourless solid, m.p. 177-9° C., 30% yield ¹ H NMR δ (CDCl₃) 1.2-1.7(8H, m, 4×CH₂), 2.53 (2H, t, J=8 Hz, CH₂ Ar), 2.95 (1H, dd, J=5, 15 Hz,H₃), 3.21 (2H, m, NCH₂), 3.44 (1H, dd, J=2, 15 Hz, H₃), 3.72, 4.10 (each1H, d, J=17 Hz, NCH₂), 3.89, 4.04 (each 1H, d, J=13 Hz, SOCH₂), 4.54(1H, m, H₄), 6.74 (1H, br s, NH), 7.0-7.4 (9H, m, Ph--H+BrPh--H);ν_(c=o) 1792 cm⁻¹ Found: C, 56.9; H, 5.7; N, 5.6%; C₂₄ H₂₉ BrN₂ O₃ Srequires: C, 57.0; H, 5.8, N, 5.5%

EXAMPLE 121N-(6-(4-Bromophenyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide(Diastereoisomer 2)

Colourless solid, m.p. 111-3° C., 45% yield ¹ H NMR δ (CDCl₃), 1.2-1.7(8H, m, 4×CH₂), 2.54 (2H, t, J=8 Hz, CH₂ Ar), 2.88 (1H, dd, J=2, 15 Hz,H₃), 3.18 (1H, dd, J=5, 15 Hz, H₃), 3.25 (2H, m, NCH₂), 3.89, 4.24(each1H, d, J=17 Hz, NCH₂), 3.98, 4.19 (each 1H, d, J=13 Hz, SOCH₂), 4.62(1H, m, H₄), 7.0-7.4 (10H, m, Ph--H+BrPh--H+NH); ν_(c=o) 1793 cm⁻¹Found: C, 57.0; H, 5.7; N, 5.6%; C₂₄ H₂₉ BrN₂ O₃ S requires: C, 57.0; H,5.8; N, 5.5%

EXAMPLE 122N-(6-(4-Fluorophenyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide(Diastereoisomer 1)

Colourless solid, m.p. 163-4° C., 33% yield ¹ H NMR δ (CDCl₃) 1.2-1.7(8H, m, 4×CH₂), 2.55 (2H, t, J=8 Hz, CH₂ Ar), 2.96 (1H, dd, J=5, 15 Hz,H₃), 3.22 (2H, m, NCH₂), 3.46 (1H, dd, J=2, 15 Hz, H₃), 3.71, 4.12 (each1H, d, J=17 Hz, NCH₂), 3.89, 4.06 (each 1H, d, J=13 Hz, SOCH₂), 4.53(1H, m, H₄), 6.70 (1H, br s, NH), 6.9, 7.1 (4H, 2×m, FPh--H), 7.25, 7.35(5H, 2×m, Ph--H); ν_(c=o) 1791 cm⁻¹ Found: C, 64.8; H, 6.5; N, 6.2%; C₂₄H₂₉ FN₂ O₃ S requires: C, 64.8; H, 6.6; N, 6.3%

EXAMPLE 123N-(6-(4-Fluorophenyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide(Diastereoisomer 2)

Colourless solid, m.p. 118-9° C., 35% yield ¹ H NMR δ (CDCl₃) 1.2-1.7(8H, m, 4×CH₂), 2.56 (2H, t, J=8 Hz, CH₂ Ar), 2.89 (1H, dd, J=2, 15 Hz,H₃), 3.18 (1H, dd, J=5, 15 Hz, H₃), 3.25 (2H, m, NCH₂), 3.89, 4.24(each1h, d, J=17 Hz, NCH₂), 3.99, 4.19 (each 1H, d, J=13 Hz, SOCH₂), 4.60(1H, m, H₄), 6.93, 7.10 (4H, 2×m, FPh--H), 7.2-7.5 (6H, m, Ph--H+NH);ν_(c=o) 1793 cm⁻¹ Found: C, 64.8; H, 6.5; N, 6.2% C₂₄ H₂₉ FN₂ O₃ Srequires: C, 64.8; H, 6.6; N, 6.3%

EXAMPLE 124 6-Phenylhexyl (4-benzylsulphinyl-2-oxo-azetidin-1-yl)acetate(2:1 Diast 2: Diast 1)

Colourless crystals, m.p. 64-7° C., 80% yield Found: C, 66.5; H,6.8;N,3.3%; C₂₄ H₂₉ NO₄ S.0.8CH₂ Cl₂ requires: C,66.6; H, 6.9; N, 3.1%

EXAMPLE 1256-(4-Chlorophenyl)hexyl-(4-benzylsulphinyl-2-oxo-azetidin-1yl] acetate

Colourless oil, 25% yield Found: C, 61.3; H, 6.1; N, 3.1%; C₂₄ H₂₈ ClNO₄S 0.14CH₂ Cl₂ requires: C, 61.2; H, 6.0; N, 3.0%

EXAMPLE 126 1-(9-Phenylnonyl)-4-benzylsulphinyl-2-oxoazetidine(Diastereoisomer 1)

Colourless solid, m.p. 87-8° C., 10% yield ¹ H NMR δ (CDCl₃) 1.2-1.7(14H, m, 7×CH₂), 2.59 (2H, t, J=8 Hz, CH₂ Ar), 2.85, (1H, dd, J=5, 15Hz, H₃), 3.25 (2H, m, NCH₂), 3.40 (1H, dd, J=2, 15 Hz, H₃), 3.86, 4.01(each 1H, d, J=13 Hz, SOCH₂), 4.33 (1H, m, H₄), 7.15-7.45 (10H, m,Ph--H) ν_(c=o) 1777 cm⁻¹

EXAMPLE 127 1-(9-Phenylnonyl)-4-benzylsulphinyl-2-oxoazetidine (75%Diastereoisomer 2)

Colourless solid, m.p. 59-61° C., 34% yield ¹ H NMR δ (CDCl₃) Dia 2)1.2-1.7 (14H, m, 7×CH₂), 2.46 (1H, dd, J=2, 15 Hz, H₃), 2.59 (2H, t, J=8Hz, CH₂ Ar), 2.96, (1H, dd, J=5, 15 Hz, H₃), 3.37 (2H, m, NCH₂), 3.98,4.07 (each 1H, d, J=13 Hz, SOCH₂), 4.37 (1H, m, H₄), 7.15-7.40 (10H, m,Ph--H)

EXAMPLE 128N-[6-(4-Methylphenyl)-hexyl]-[4-benzylsulphinyl-2-oxo-azetidin-1-yl]-acetamide

Colourless solid, m.p. 156-7° C., 29% yield Found: C, 67.9; H, 7.1; N,6.3%; C₂₅ H₃₂ N₂ O₃ S requires: C, 68.2; H, 7.3; N, 6.4%

EXAMPLE 129N-[6-(4-Methylphenyl)-hexyl]-[4-benzylsulphinyl-2-oxo-azetidin-1-yl]-acetamide

Colourless solid, m.p. 94-5° C., 59% yield Found: C, 68.0; H, 7.2; N,6.3%; C₂₅ H₃₂ N₂ O₃ S requires: C, 68.2; H, 7.3; N, 6.4%

EXAMPLE 130N-(6(4-chlorophenyl)hex-1-yl)-((4-carboxybenzylsulphinyl)-2-oxoazetidin-1-yl)acetamide(diastereoisomer 2)

A solution ofN-(6-[4-chlorophenyl]hex-1-yl-(4-allyloxycarbonylbenzylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereoisomer 2) 1.25 g), tetrakis triphenylphosphinepalladium(0) (80 mg), triphenylphosphine (635 mg) and pyrrolidine (171mg) in dichloromethane (100 ml) was stirred at 25° C. for 16 h. Thereaction mixture was then chromatographed (fine silica,dichloromethane-50% acetone in dichloromethane), without concentration,to giveN-(6-(4-chlorophenyl)hex-1-yl)-((4-carboxybenzylsulphinyl)-2-oxoazetidin-1-yl)acetamide(diastereoisomer 2) as a white solid, m.p. 195-197° C., 62% yield Found:C, 59.0; H, 5.7; N, 5.5%; C₂₅ H₂₉ ClN₂ O₃ S 0.1H₂ O requires: C, 59.2;H, 5.8; N, 5.5%

The following sulfones (Examples 131-144) were prepared by treatment ofthe corresponding sulfide or sulfoxide with an excess of m-CPBA asdescribed in Example 4.

EXAMPLE 131N-[6-(4-Fluorophenyl)hexyl]-4-(4-methoxybenzylsulphonyl)-2-oxoazetidin-1-ylacetamide

Colourless crystals, m.p. 115-8° C., 37% yield Found: C, 61.0; H, 6.3;N, 5.7%; C₂₅ H₃₁ FN₂ O₅ S requires: C, 61.2; H, 6.4; N, 5.7%

EXAMPLE 132N-(6-(2,4-Difluorophenyl)hexyl)-4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide

Colourless solid, m.p. 130-131° C., 68% yield ¹ H NMR δ (CDCl₃) 1.3-1.36(4H, m, 4×CH₂), 1.50-1.60 (4H, m, 4×CH₂), 2.58 (2H, t, J=7.6 Hz, PhCH₂),2.97, 3.03 (1H, dd, J=2.6, 15.42 Hz, H₃), 3.08, 3.14 (1H, dd, J=5.0,15.4 Hz, H₃), 3.24 (2H, m, NHCH₂), 3.84, 3.94 (each 1H, d, J=16.9 Hz,NCH₂), 4.31, 4.37 (each 1H, d, J=14.3 Hz, SO₂ CH₂), 4.81 (1H, m, H₄),6.0 (1H, m, NH), 6.72-7.44 (9H, m, 2Ph--) ν_(c=o) 1797 cm⁻¹ Found: C,60.1; H, 5.9; N, 5.9%; C₂₄ H₂₈ F₂ N₂ O₄ S requires: C, 60.2; H, 5.9; N,5.9%

EXAMPLE 133N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxybenzylsulphonyl)-2-oxoazetidin-1-ylacetamide

Colourless crystals, m.p. 118-20° C., 94% yield Found: C, 59.0; H, 6.1;N, 5.5%; C₂₅ H₃₁ ClN₂ O₅ S requires: C, 59.2; H, 6.2; N, 5.5%

EXAMPLE 134N-(6-(3,4-Difluorophenyl)hexyl)-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide

Colourless solid, m.p. 114-115° C., % yield ¹ H NMR δ (CDCl₃) 1.3-1.36(4H, m, 4×CH₂), 1.50-1.60 (4H, m, 4×CH₂), 2.55 (2H, t, J=7.6 Hz, PhCH₂),2.97, 3.03 (1H, dd, J=2.5, 15.4 Hz, H₃), 3.08, 3.14 (1H, dd, J=5.0, 15.4Hz, H₃), 3.24 (2H, m, NHCH₂), 3.84, 3.94 (each 1H, d, J=16.9 Hz, NCH₂),4.31, 4.37 (each 1H, d, J=14.2 Hz, SO₂ CH₂), 4.83 (1H, m, H₄), 6.04 (1H,m, NH), 6.82-7.44 (9H, m, 2Ph--H) ν_(c=o) 1797 cm⁻¹ Found: C, 60.1; H,5.9; N, 5.9%; C₂₄ H₂₈ F₂ N₂ O₄ S requires: C, 60.2; H, 5.9; N, 5.9%

EXAMPLE 136 N-(7-phenylhept-1-yl)-4-benzylsulphonyl-2-oxoazetidin-1-ylacetamide

Form white crystalline solid, m.p 114-115° C., 85% yield Found: C, 64.9;H, 6.9; N, 6.1%; C₂₅ H₃₂ N₂ O₄ S 0.3 H₂ O requires: C, 65.0; H, 7.1; N,6.1%

EXAMPLE 137N-[6-(4-Chlorophenyl)hexyl]-(4-(4-carboxybenzylsulphonyl)-2-oxo-azetidin-1-yl)acetamide

Colourless crystals, m.p. 137-4° C., 40% yield. Found: C, 56.9; H, 5.7;N, 5.1%; C₂₆ H₃₁ ClN₂ O₆ S 0.5H2O requires: C, 56.8; H, 6.0; N, 5.1%

EXAMPLE 138N-[5-(4-Chlorophenyl)pentyl]-4-benzylsulphonyl-2-oxo-azetidin-1ylacetamide

Colourless crystals, m.p. 109-10° C., 81.7% yield Found: C, 59.6; H,5.7; N, 6.0%; C₂₃ H₂₇ ClN₂ O₄ S requires: 59.7; H, 5.89; N, 6.1%

EXAMPLE 139N-[5-(2-Chlorophenyl)hexyl]-4-benzylsulphonyl-2-oxo-azetidin-1ylacetamide

Colourless crystals, m.p. 81-3° C., 84% yield Found: C, 60.5; H,6.1;N,5.9%; C₂₄ H₂₉ ClN₂ O₄ S. requires: C,60.5; H,6.1; N,5.9%

EXAMPLE 140N-(6-(4-Fluorophenyl)hexyl)-4-benzylsulphonyl-2-oxoazetidin-1-ylacetamide

Colourless solid, m.p. 132-3° C., 76% yield ¹ H NMR δ (CDCl₃) 1.2-1.6(8H, m, 4×CH₂), 2.57 (2H, t, J=8 Hz, CH₂ Ar), 3.02 (1H, dd, J=2, 15 Hz,H₃), 3.10 (1H, dd, J=5, 15 Hz, H₃), 3.25 (2H, m, NCH₂), 3.85, 3.94 (each1H, d, J=17 Hz, NCH₂), 4.34 (2H, s, SO₂ CH₂), 4.82 (1H, m, H₄), 6.0 (1H,br s, NH), 6.9, 7.15 (4H, 2×m, FPh--H), 7.4 (5H, m, Ph--H); ν_(c=o) 1797cm⁻¹ Found: C, 62.5; H, 6.3; N, 6.2%; C₂₄ H₂₉ FN₂ O₄ S requires: C,62.6; H, 6.4; N, 6.1%

EXAMPLE 141 6-Phenylhexyl-[4-benzylsulphonyl-2-oxo-azetidin-1-yl]acetate

Colourless oil, 2.3% yield ¹ H NMR δ (CDCl₃) 1.32-1.65 (8H, m, 4×CH₂),2.60 (2H, t,J=7.64 Hz, ArCH₂), 2.95 (1H, dd, 2.35 Hz, 13.35 Hz, H3a),3.11 (1H, dd, J=5.12 Hz, 15.39 Hz, H_(3b)), 3.72, 4.27 (1H each, J=18.3Hz, NCH₂), 4.34 (2H, s, SCH₂ Ph), 4.11 (2H, m, OCH₂), 4.91 (1H, dd,J=2.36 Hz, 5.08 Hz, H₄), 7.15-7.43 (10H, m, 10×ArH)

EXAMPLE 1426-(4-Chlorophenyl)hexyl-(4-benzylsulphonyl-2-oxo-azetidin-1-yl]acetate

Colourless crystals, m.p. 77-9° C., 50% yield Found: C, 60.3; H, 5.9; N,3.0%; C₂₄ H₂₈ ClNO₅ S requires: C, 60.3; H, 5.9; N, 2.9%

EXAMPLE 143 1-(9-Phenylnonyl)-4-benzylsulphonyl-2-oxoazetidine

Colourless solid, m.p. 69-70° C., 59% yield ¹ H NMR δ (CDCl₃) 1.2-1.7(14H, m, 7×CH₂), 2.59 (2H, t, J=8 Hz, CH₂ Ph), 2.92 (1H, dd, J=2, 15 Hz,H₃) 3.1 (2H, m, H₃ +NCH₂), 3.4 (1H, m, NCH₂), 4.28 (2H, s, SCH₂), 4.50(1H, m, H₄), 7.1-7.5 (10H, m, Ph--H); ν_(c=o) 1782 cm⁻¹ Found: C, 70.0;H, 7.6; N, 3.4%; C₂₅ H₃₃ NO₃ S requires: C, 70.2; H, 7.8; N, 3.3%

EXAMPLE 144N-[6-(4-Methylphenyl)-hexyl]-[4-benzylsulphonyl-2-oxo-azetidin-1-yl]-acetamide

Colourless solid, m.p. 125-6° C., 67% yield Found: C, 65.3; H, 6.8; N,6.0%; C₂₅ H₃₂ N₂ O₄ S requires: C, 65.8; H, 7.1; N, 6.1%

EXAMPLE 145N-(6-Phenylhexanoyl)-(4-benzylthio-2-oxoazetidin-yl)acetamide

a. 4-Benzylthio-2-oxoazetidin-1-yl)acetamide

Book No. 50516/061

A solution of (4-benzylthio-2-oxoazetidin-1-yl)acetic acid (1.0 g, 3.98mmol) in dry tetrahydrofuran (25 ml), stirred at 10° C. under a nitrogenatmosphere, was treated with 1,1'-carbonyldidimidazole (0.71 g, 4.38mmol) and stirred at room temperature for 2 h. Ammonia gas was bubbledthrough the reaction for 30 minutes. The reaction was stirred for afurther 60 minutes, diluted with ethyl acetate (75 ml), washed withaq.sat NaHCO₃ solution, brine, dried (MgSO₄) and evaporated underreduced pressure. Purification by column chromatography eluted with 20:1CH₂ Cl₂ :MeOH gave the product as a colourless solid, m.p. 127-128° C.(0.92 g, 92% yield). ¹ nmr δ (CDCl₃) 2.93,2.99 1H, dd, J=2.4, 15.4 Hz,H₃), 3.36,3.42 (1H, dd, J=6.2, 15.4 Hz, H₃), 3.47, 3.79 (each 1H, d,J=17 Hz, NCH₂), 3.82 (2H, s, SCH₂), 4.85 (1H, m, H₄), 5.62 (1H, bs, NH),6.97 (1H, bs. NH), 7.23-7.38 (5H, m, Ph--H)

b. 6-Phenylhexanoyl chloride

6-Phenylhexanoic acid (2.5 g, 13 mmol) was treated with thionyl chloride(3.0 ml, 41.1 mmol) and stirred under reflux for 3 h. The mixture wasevaporated under reduced pressure to remove thionyl chloride and thendistilled at 92-95° C./0.1 mbar to give the product as a colourless oil(2.57 g, 94%).

c. N-(6-Phenylhexanoyl)-(4-benzylthio-2-oxoazetidin-yl)acetamide

A solution of (4-benzylthio-2-oxoazetidin-1-yl)acetamide (0.63 g, 2.52mmol) in dry THF (15 ml) was added to a suspension of sodium hyride (60%in oil, 0.10 g, 2.5 mmol) in dry THF at -10° C. under a nitrogenatmosphere. The reaction was stirred at -10° C. for 10 minutes and wasthen treated with a solution of 6-phenylhexanoyl chloride (0.58 g, 2.75mmol) in dry THF (5 ml) dropwise over 2 minutes maintaining thetemperature at -10° C. The cooling bath was removed an after stirringfor 60 minutes the reaction was treated with sodium hydride (50 mg, 1.25mmol) and 6-phenylhexanoyl chloride (0.29 g, 1.38 mmol) in dry THF (2ml). The reaction was stirred for 60 minutes, poured into ice/brine (100ml), extracted with ethyl acetate (2×50 ml). The organic extracts werecombined, washed with aq. sat. NaHCO₃ solution, brine, dried (MgSO₄) andevaporated under reduced pressure to an orange oil. Purification byrepeated column chromatography eluted with hexane:ethyl acetate (3:1 to1:1) gave the product as a colourless oil (0.22 g, 21% yield, contains10% 6-phenylhexanoic acid) ¹ H nmr δ (CDCl₃) 1.3-1.7 (6H, m, 3×CH₂),2.44 (2H, t, J=7.4 Hz, NHCOCH₂), 2.62 (2H, t, J=7.6 Hz, PhCH₂), 2.96,3.02 (1H, dd, J=2.4, 15.3 Hz, H₃), 3.39, 3.45 (1H, dd, J=5.1, 15.3 Hz,H₃), 3.61, 4.32 (each 1H, d, J=18.8 Hz, NCH₂ CO), 3.76 (2H, m, SCH₂),4.9 (1H, m, H₄), 7.1-7.3 (10H, m, 2×Ph--H), 8.17 (1H, m, NH)

EXAMPLE 146N-(6-Phenylhexanoyl)-(4-benzylsulphinyl-2-oxoazetidin-yl)acetamide

Treatment ofN-(6-Phenylhexanoyl)-(4-benzylthio-2-oxoazetidin-yl)acetamide with mCPBAas in Example 2 gave the title compound as an 50:50 mixture ofdiastereoisomers. Colourless solid, m.p. 153-156° C., 37% yield ¹ H nmrδ (CDCl₃) 1.36 (4H, m, 2×CH₂), 1.64 (8H, m, 4×CH₂), 3.39 (4H, m2×PhCH₂), 2.48, 2.52 (1H, dd, J=2.4, 15.2 Hz, H₃), 2.60 (4H, m, 2×NCH₂),2.96, 2.99 (1H, dd, J=4.8, 14.8 Hz, H_(3')), 3.03, 3.07 (1H, dd, J=5.2,15.2 Hz, H₃), 3.39, 3.43 (1H, J=2.0, 14.8 Hz, H_(3')), 3.9-4.6 (8H, m,2×NCH₂, 2×SOCH₂), 4.72 (1H, m, H_(4')), 4.81 (1H, m, H₄), 7.16-7.40(20H, m, 4×Ph--H), 8.49 (1H, s, NH), 9.01 (1H, s, NH); ν_(c=o) 1787 cm⁻¹Found: C, 65.3; H, 6.4; N, 6.4%; C₂₄ H₂₈ N₂ O₄ S requires: C, 65.4, H,6.4; N, 6.4%

EXAMPLE 147N-(5-Phenylpentyloxy)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Treatment of (4-benzylthio-2-oxo)azetidin-1-ylacetic acid withN-(5-phenylpentyl)hydroxylamine by the method described for Examples 1and 86 gaveN-(5-phenylpentyloxy)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide as acolourless oil in 55% yield. ¹ H NMR δ (DMSO 350K) 1.31-1.43 (2H, m,CH₂), 1.53-1.67 (4H, m, 2×CH₂), 2.58 (2H, t, J=7.6 Hz, PhCH₂), 2.85,2.91 (1H, dd, J=2.4, 15.0 Hz, H₃), 3.41 (1H, d, J=18.2 Hz, 1 of NCH₂),3.74-3.91 (5H, m, 1 of NCH₂, SCH₂, NHOCH₂), 4.87 (1H, m, H₄), 7.10-7.35(10H, m, 2×Ph--H), 10.8 (1H, m, NH).

Treatment ofN-(5-phenylpentyloxy)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide withm-CPBA gave the following two compounds after work up as described forExamples 2 and 3.

EXAMPLE 148N-(5-Phenylpentyloxy)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acatamide(Diastereoisomer 1)

Colourless solid, m.p. 178-179° C., 23% yield ¹ H NMR δ (DMSO 350K)1.34-1.38 (2H, m, CH₂), 1.56-1.62 (4h, M, 2×CH₂), 2.58 (2H, t, j=7.6 Hz,PhCH₂), 3.0-3.17 (2H, m, H₃), 3.65, 3.40 (each 1H, m, SOCH₂), 3.75 (2H,t, J=6.5 Hz, NHOCH₂), 3.85, 4.10 (each 1H, d, J=18 Hz, NCH₂), 4.87 (1H,m, H₄), 7.14-7.35 (10H, m, 2×Ph--H), 10.9 (1, m, NH) ν_(c=o) 1777 cm⁻¹Found: C, 63.8; H, 6.5; N, 6.5%; C₂₃ H₂₈ N₂ O₄ S (+1.0% H₂ O) requires:C, 63.8; H, 6.6; N, 6.5%

EXAMPLE 149N-(5-Phenylpentyloxy)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acatamide(Diastereoisomer 2)

Colourless oil, 39% yield ¹ H NMR δ (DMSO 350K) 1.36 (2H, m, CH₂),1.56-1.61 (4H, m, 2×CH₂), 2.58 (2H, t, J=7.6 Hz, PhCH₂), 2.9, 3.2 (2H,m, H₃), 3.75 (2H,t,J=6.6 Hz, NHOCH₂), 3.9, 4.05 (each 1H, m, SOCH₂),4.04, 4.20 (each 1H, d, J=12.9 Hz, NCH₂), 4.79 (1H, m, H₄), 7.16-7.37(10H, m, 2×Ph--H), 10.95 (1H,m, NH); ν_(c=o) 1788 cm⁻¹ Found: C, 63.7;H, 6.6; N, 6.2%; C₂₃ H₂₈ N₂ O₄ S(+1.4% C₄ H₈ O₂, 1.0% H₂ O) requires C,63.7; H, 6.7; N, 6.4%

EXAMPLE 150R--N-(6-(4-Chlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Treatment of R-(-)-(4-benzythio-2-oxoazetidin-1-yl)acetic acid [preparedfrom the corresponding racemic acid by recrystallisation of the saltformed with chinchonidine [α]_(D) ²⁵ =-43° (c=1, CHCl₃)] withdicyclohexylcarbidimide and 6-(4-chlorophenyl)hexylamine by theprocedure described for Example 29 gaveR--N-(6-{4-Chlorophenyl}hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamideas a colourless sold, m.p. 71° C., 83% yield. ¹ H nmr δ (CDCl₃) 1.33(4H, m, 2×CH₂), 1.47-1.6 (4H, m, 2×CH₂), 2.56 (2H, t, J=7.6 Hz, PhCH₂),2.92, 2.97 (1H, dd, J=2.4, 15.4 Hz, H₃), 3.22-3.24 (2H, m, NHCH₂), 3.33,3.39 (1H, dd, J=5.2, 15.4 Hz, H₃), 3.54, 3.72 (each 1H, d, J=16.8 Hz,NCH₂), 3.81 (1H, s, SCH₂), 4.80 (1H, m, H₄), 6.11 (1H, m, NH),7.07-7.33(9H, m, 2×Ph--H) ν_(c=o) 1776 cm⁻¹ ; [α]_(D) =+36.0° (c=1.1%w/v in CHCl₃) at 25° C. Found: C, 64.8; H, 6.5; N, 6.4%; C₂₄ H₂₉ ClN₂ O₂S requires: C, 64.8; H, 6.6; N, 6.3%

EXAMPLE 151S--N-(6-{4-Chlorophenyl}hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

4S-(4-benzylthio-2-oxoazetidin-1-yl)acetic acid, [α]_(D) ²⁵ =+34°(c=1.1%, CHCl₃) was prepared from the corresponding racemic acid byrecrystallisation of the salt formed with cinchonine or brucine. Thischirally pure acid was treated with 4-chlorophenyl)hexylamine by theprocedure of Example 29 to give the title compound as a colourlesssolid, m.p. 69-70° C., 73% yield. ¹ H nmr δ (CDCl₃) 1.33 (4H, m 2×CH₂),1.47-1.6 (4H, m, 2×CH₂), 2.56 (2H, t, J=7.6 Hz, PhCH₂), 2.93, 2.97 (1H,dd, J=2.4, 15.2 Hz, H₃), 3.22-3.24 (2H, m, NHCH₂), 3.35, 3.39 (1H, dd,J=5.2, 15.2 Hz, H₃), 3.54, 3.72 (each 1H, d, J=16.8 Hz, NCH₂), 3.81 (1H,s, SCH₂), 4.80 (1H, m, H₄), 6.11 (1H, m, NH), 7.05-7.36 (9H, m,2×Ph--H); ν_(c=o) 1776 cm⁻¹ ; [α]_(D) =-36.3° (C=0.9% w/v in CHCl₃) at25° C. Found: C, 64.5; H, 6.5; N, 6.3%; C₂₄ H₂₉ ClN₂ O₂ S requires: C,64.8; H, 6.6; N, 6.3%

EXAMPLE 1524R,SR-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1yl-acetamide

4R-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(0.5 g) was treated with (+)-(8,8-Dichlorocamphorylsulfonyl)oxaziridine(0.3 g) in dichlorometnane (70 ml) at 25° C. for 16 h to give the titlecompound after chromatography (silica/EtOAc) as a colourless solid, m.p.159-160° C., (0.21 g, 41% yield). ¹ nmr δ (CDCl₃) 1.3-1.6 (8H, m,4×CH₂), 2.55 (2H, t, J=7.6 Hz, PhCH₂), 2.93, 2.98 (1H, dd, J=4.8, 14.8Hz, H₃), 3.22 (2H, m, NHCH₂), 3.44, 3.48 (1H, dd, J=2.2, 14.8 Hz, H₃),3.68, 4.13 (each 1H, d, J=17.4 Hz, NCH₂), 3.88, 4.05 (each 1H, d, J=12.8Hz, SOCH₂), 4.50 (1H, m, H₄), 6.65 (1H, m, NH), 7.07-7.40 (9H, m,2×Ph--H); ν_(c=o) 1791 cm⁻¹ ; [α]_(D) =-166.91° (c=1.08% w/v in CHCl₃)at 25° C. Found: C, 62.2; H, 6.3; N, 6.1%; C₂₄ H₂₉ ClN₂ O₃ requires: C,62.5; H, 6.3; N, 6.1%

EXAMPLE 1534S,SS-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1yl)acetamide

4S-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(1 g) was treated with (-)-(8,8-dichlorocamphorylsulfonyl)oxaziridine(0.67 g) in dichlorometnane (75 ml) at 25° C. for 16 h to give the titlecompound, after chromatography (silica/EtOAc), as a colourless solid,m.p. 159° C., (0.95 g, 83% yield); ¹ H nmr δ (CDCl₃) 1.2-1.6 (8H, m,4×CH₂), 2.55 (2H, t, J=7.6 Hz, PhCH₂), 2.93, 2.99 (1H, dd, J=4.8, 14.8Hz, H₃), 3.22 (2H, m, NHCH₂), 3.44, 3.49 (1H, dd, J=2.2, 14.8 Hz, H₃),3.68, 4.13 (each 1H, d, J=17.4 Hz, NCH₂), 3.88, 4.05 (each 1H, d, J=13.1Hz, SOCH₂), 4.50 (1H, m, H₄), 6.65 (1H, m, NH), 7.07-7.40 (9H, m,2×Ph--H); ν_(c=o) 1791 cm⁻¹ ; [α]_(D) =+169.2° (c=1.0% w/v in CHCl₃) at25° C. Found: C, 62.4; H, 6.3; N, 6.1%; C₂₄ h₂₉ ClN₂ O₃ requires: C,62.5; H, 6.3; N, 6.1%

EXAMPLE 1544R,SS-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(diastereoisomer 2)

Treatment of4R-N-(6-(4-chlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide(0.95 g) with mCPBA (0.355 g/65% pure) in dichloromethane (40 ml) by theprocedure of Example 30 gave the title compound as a colourless solid,m.p. 139-140° C., 16% yield after repeated recrystallisation frombutanone; ¹ H nmr δ (CDCl₃) 1.33 (4H, m, 2×CH₂), 1.5-1.65 (4H, m,2×CH₂), 2.56 (2H, t, J=7.6 Hz, PhCH₂), 2.87, 2.91 (1H, dd, J=2.4, 15.6Hz, H₃), 3.16, 3.20 (1H, dd, J=5.2,15.6 Hz, H₃), 3.22-3.32 (2H, m,NHCH₂), 3.87, 4.26 (each 1H, d, J=16.8 Hz, NCH₂), 3.97, 4.18 (each 1H,d, J=13.2 Hz, SOCH₂), 4.60 (1H, m, H₄), 7.08-7.41 (10H, m, 2×Ph--H, NH);ν_(c=o) 1793 cm⁻¹ ; Found: C, 61.6; H, 6.1; N, 6.1%; C₂₄ H₂₉ ClN₂ O₃ S.0.26 H₂ O requires: C, 61.9; H, 6.4; N, 6.0%

EXAMPLE 1554R,SS-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1yl)acetamide(diastereoisomer 2)

4R-N-(6-(4-chlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide(52.2 g) was treated with mCPBA (26.3 g/65% pure) in dichloromethane(1500 ml) at -70 to -74° C. for 120 min. After work-up with aqueoussodium sulfite and sodium bicarbonate the organic layer was dried andevaporated to give an approximately 65:35 mixture of sulfoxidediastereoisomers (2:1) (53.1 g). This was combined with other similarbatches of material and separated by preparative HPLC on a Septech 800Cinstrument using a Merck 50 mm selfpacker column with Lichrosphere 10 umsilica (220 g) as stationary phase and 60% ethanol/40% n-hexane aseluant to give the title compound as a colourless solid, m.p. 139-140°C., 35% overall yield. [α]_(D) =+126.4° (c=1.004% w/v in CHCl₃) at 25°C.; Found: C, 62.5; H, 6.2; N, 6.2% C₂₄ H₂₉ ClN₂ O₃ S requires: C, 62.5;H, 6.3; N, 6.1%; spectra same as for Example 154.

EXAMPLE 1564R,SS-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(diastereoisomer 2)

R-(+)-1,1'-Binaphthol (0.256 g) was suspended in toluene (20 ml) at 25 Cand Ti(OiPr)4 (0.134 ml) and water (0.168 ml) added. After 1 h4R-N-(6-(4-chlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide(2.07 g) in toluene (12 ml) was added and the mixture stirred for 30min. t-Butylhydroperoxide (1.36 ml) was added and the mixture stirredfor 66 h. After chromatography a 6:1 mixture of sulfoxidediastereoisomers (4R,SS:4R,SR) was isolated (1.6 g, 75%). The 4R,SRisomer was removed by addition of 0.222 g of4S,SS-N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamideto the mixture, crystallisation of the 4R,SR/4S,SS racemate from themixture and crystallisation of4R,SS-N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(1.19 g, 55%, colourless solid, m.p. 139-140° C.) from the motherliquor. Spectra and physical properties were the same as those ofExample 154.

EXAMPLE 1574R,SS-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(diastereoisomer 2)

a. R-(-) (4-Benzylsulfinyl-2-oxoazetidin-1-yl) acetic acid

9.11 g of R-(-)-(4-Benzylthio-2-oxoazetidin-1-yl)acetic acid wasdissolved in 250 ml dry dichloromethane and cooled to -70° C. Ozone gaswas then passed through the solution in pulses until all the startingmaterial was consumed. The reaction mixture was then purged with oxygenand allowed to warm to room temperature. Triphenyl phosphine (˜) 10 mgwas added to the solution which was then evaporated to an oil/solid(10.7 g). The two component mixture was then triturated with chloroform(100 ml) at room temperature causing the oil to dissolve. The solid wasfiltered off and found to be predominantly diastereoisomer 1 (4R, SR)(4.55 g, 46%) (˜90% dia 1), m.p. 142-144° C. The filtrate was theevaporated to dryness to yield a glass which was predominantly (94%)diastereoisomer 2 (4R, SS) by hplc. (4.6 g 47%) m.p. indeterminate. ¹ Hnmr δ 2.95 (1H, dd, H₃), 3.29 (1H, dd, H₃), 3.78-4.24 (4H,m, NCH₂,SOCH₂), 4.81 (1H, m, H₄), 7.36 (5H, m, Ar-H)

b. 4-chlorophenylhexyl amine (1.31 g, 0.0074 mol) in drydimethylformamide was added to a mixture of 1-hydroxybenzotriazole (0.96g), N,N'-dicyclohexylcarbodiimide (1.52 g) and the predominantly4R,SS-(-)-4-(benzylsulphinyl-2-oxoazetidin-1-yl)acetic acid (2 g),prepared in (a) above, in dry dimethylformamide (50 ml) at roomtemperature and allowed to stir for two hours. After aqueous work-up,evaporation of the organic solvnts and recrystallisation from ethylacetate the title compound was isolated in a 94:6 mixture with thecorresponding 4R,SR isomer (1.66 g, 55%) m.p. 133-134° C.

EXAMPLE 1584S,SR-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(diastereoisomer 2)

The title compound was prepared from4S-N-(6-(4-chlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamideusing the procedure described in Example 156 but substitutingS-(-)-1,1'-binaphthol for R-(+)-1,1'-binaphthol and4R,SR-N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1yl)acetamidefor4S,SS-N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamideand was obtained as a colourless solid, m.p. 139-140° C., 44% yield; ¹ Hnmr δ (CDCl₃) 1.33 (4H, m, 2xCH₂), 1.5-1.65 (4H, m 2xCH₂), 2.56 (2H, t,J=7.7 Hz, PhCH₂), 2.87, 2.91 (1H, dd, J=2.4, 15.3 Hz, H₃), 3.16, 3.20(1H, dd, J=5.1,15.3 Hz, H₃), 3.22-3.32 (2H, m, NHCH₂), 3.87, 4.26 (each1H, d, J=17.1 Hz, NCH₂), 3.97, 4.18 (each 1H, d, J=13 Hz, SOCH₂), 4.60(1H, m, H₄), 7.08-7.41 (10H, m, 2xPh-H, NH); ν _(c)═o 1793 cm⁻¹ ;[α]_(D) =-124.11° (c=1.1% w/v in CHCl₃) at 25° C.; Found: C, 62.4; H,6.3; N, 6.1%; C₂₄ H₂₉ ClN₂ O₃ S requires: C, 62.5; H, 6.3; N, 6.1%

EXAMPLE 1594R-N-(6-(4-Chlorophenyl)hexyl)-(4-benzysulphonyl-2-oxoazetidin-1-yl)acetamide

The title compound was isolated by chromatography of the reactionmixture produced in Example 156 and was obtained as a colourless solid,m.p. 145° C., 18% yield; ¹ H nmr (CDCl₃) δ 1.3-1.6 (8H, m, 4xCH₂), 2.56(2H, t, J=7.6 Hz, PhCH₂), 2.96, 3.02 (1H, dd, J=2.5, 15.4 Hz, H₃), 3.09,3.13 (each 1H, d, J=5.1, 15.4 Hz, H₃), 3.24 (2H, m, NHCH₂), 3.85, 3.94(each 1H, d, J=16.9 Hz, NCH₂), 4.34 (2H, dd, J=14.2 Hz, SO₂ CH₂), 4.83(1H, m, H₄), 6.1 (1H, m, NH), 7.07-7.43 (9H, m, 2xPh-H); ν _(c)═o 1797cm⁻¹ ; [α]_(D) =-34.7° (c=1.0% w/v in CHCl₃) at 25° C.

Found: C, 60.3; H, 6.0; N, 5.9%; C₂₄ H₂₉ ClN₂ O₄ S requires: C, 60.4; H,6.1; N, 5.9%

EXAMPLE 1604S-N-(6-(4-Chlorophenyl)hexyl)-(4-benzysulphonyl-2-oxoazetidin-1-yl)acetamide

The title compound was produced by treatment of4S-N-(6-(4-chlorophenyl)hexyl)-(4-benzythio-2-oxoazetidin-1-yl)acetamidewith mCPBA as described in Example 4 and was obtained as a colourlesssolid, m.p. 147° C., 62% yield; ¹ H nmr (CDCl₃) δ 1.3-1.6 (8H, m,4xCH₂), 2.56 (2H, t, J=7.6 Hz, PhCH₂), 2.96, 3.03 (1H, dd, J=2.5, 15.4Hz, H₃), 3.09, 3.12 (each 1H, d, J=5.1, 15.4 Hz, H₃), 3.25 (2H, m,NHCH₂), 3.85, 3.94 (each 1H, d, J=16.8 Hz, NCH₂), 4.34 (2H, dd, J=14.2Hz, SO₂ CH₂), 4.83 (1H, m, H₄), 6.1 (1H, m, NH), 7.08-7.43 (9H, m,2xPh-H; ν _(c)═o 1798 cm⁻¹ ; [α]_(D) =+36.3° (c=1.1%w/v in CHCl₃) at 25°C.

Found: C, 60.3; H, 6.0; N, 5.9%; C₂₄ H₂₉ ClN₂ O₄ S requires: C, 60.4; H,6.1; N, 5.9%

EXAMPLE 1614R-(6-Phenylhexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Treatment of 4R-(4-benzylthio-2-oxo-azetidin-1-yl)acetic acid (Example84) with dicyclohexylcarbodiimide and 6-phenylhexylamine by the methoddescribed in Example 29 to give the title compound as a colourlesssolid, m.p. 46-47° C., 49% yield; ¹ H nmr δ (CDCl₃) 1.33 (4H, m, 2xCH₂),1.5-1.65 (4H, m, 2xCH₂), 2.59 (2H, t, J=7.6 Hz, PhCH₂), 2.92, 2.96 (1H,dd, J=2.4, 15.2 Hz, H₃), 3.22 (2H, m, NHCH₂), 3.35, 3.39(1H, dd, J=5.2,15.2 Hz, H₃), 3.56, 3.71 (each 1H, d, J=16.8 Hz, NCH₂), 3.81 (2H, s,SCH₂), 4.80 (1H, m, H₄), 6.0 (1H, m, NH), 7.15-7.4 (10H, m, 2xPh-H); ν_(c)═o 1776 cm⁻¹ ; [α]_(D) =+6.6° (c=1.1%w/v in ethanol) at 25° C.

Found: C, 70.0; H, 7.2; N, 6.9%; C₂₄ H₃₀ N₂ O₂ S requires: C, 70.2; H,7.4; N, 6.8%

EXAMPLE 1624R,SR-N-(6-Phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

A mixture of (S)-(-)-1,1'-Bi-2-naphthol (28 mg, 0.98 mmol) in drytoluene (2 ml) was treated with titanium IV isopropoxide (14 mg, 0.0494mmol) and water (25 mg, 1.34 mmol). The dark orange mixture was stirredfor 60 minutes and treated with a solution ofR-N-(6-phenylhexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide (200 mg,0.487 mmol) in dry toluene (1 ml). The reaction was stirred for 30minutes and then treated with tert-butylhydroperoxide (70% in water,0.14 ml, 1.02 mmol) and stirring was continued for 3.5 h. Purificationby column chromatography eluted with ethyl acetate to 15:1 ethylacetate:ethanol and recrystallisation from ethyl acetate gave theproduct as a pale yellow solid, m.p. 145° C. (0.079 g, 38% yield). ¹ Hnmr δ (CDCl₃) 1.33 (4H, m, 2xCH₂), 1.5-1.65 (4H, m, 2xCH₂), 2.59 (2H, t,J=7.8 Hz, PhCH₂), 2.93, 2.97 (1H, dd, J=4.8, 14.8 Hz, H₃), 3.22 (2H, m,NHCH₂), 3.45, 3.48 (1H, dd, J=2.4,14.8 Hz, H₃), 3.70, 4.12 (each 1H, d,J=17.2 Hz, NCH₂), 3.88, 4.06 (each 1H, d, J=12.8 Hz, SOCH₂), 4.50 (1H,m, H₄), 6.65 (1H, m, NH), 7.16-7.4 (10H, m, 2xPh-H); ν _(c)═o 1789 cm⁻¹

Found: C, 65.7; H, 6.7; N, 6.3%; C₂₄ H₃₀ N₂ O₃ S requires: C, 67.6; H,7.1; N, 6.6%

EXAMPLE 163N-(6-{4-Fluorophenyl}hexyl)-4-(4-allyloxycarbonylbenzylthio-2-oxoazetidin-1-yl)acetamide

Treatment of 4-(4-allyloxycarbonylbenzylthio)azetidin-2-one withN-(6-(-4-fluorophenyl)hexyl)-1-bromoacetamide by the method described inExample 85a gave the title compound as a colourless oil, 43% yield. ¹ HNMR δ (CDCl₃) 1.30-160 (8H, m, 4xCH₂), 2.55 (2H, t, J=7.6 Hz, CH₂ Ph),2.90, 2.97 (1H, dd, J=2.4, 15.4 Hz, H₃), 3.23 (2H, m, NHCH₂), 3.35, 3.41(1H, dd, J=5.1, 15.4 Hz, H₃), 3.53, 3.78 (each 1H, d, J=16.6 Hz, NCH₂),3.86 (2H, s, SCH₂), 4.83 (3H, m, CO₂ CH₂, H₄), 5.37 (2H, m, CH₂ ═CH),6.0 (2H, m, NH, CH₂ ═CH), 6.94 (2H, m, 4-FPh-H), 7.10 (2H, m, 4-FPh-H),7.39 (2H, d, J=8.3 Hz, 4-CO₂ allylPh-H), 8.02 (2H, d, J=8.3 Hz, 4-CO₂allylPh-H)

Treatment ofN-(6-(4-fluorophenyl)hexyl)-4-(4-allyloxycarbonylbenzylthio-2-oxoazetidin-1-yl)acetamidewith mCPBA followed by recrystallisation as described for Example 2 and3 gave the compounds described in Examples 164 and 165.

EXAMPLE 164N-(6-{4-Fluorophenyl}hexyl)-4-(4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 1)

Colourless solid, m.p. 190-191° C., 24% yield. ¹ H NMR δ (CDCl₃)1.30-1.60 (8H, m, 4xCH₂), 2.55 (2H, t, J=7.6 Hz, CH₂ Ph), 2.95, 2.98(1H, dd, J=4.8, 14.8 Hz, H₃), 3.24 (2H, m, NHCH₂), 3.42, 3.46 (1H, dd,J=2.4, 14.8 Hz, H₃), 3.76, 4.09 (each 1H, d, J=17.2 Hz, NCH₂), 3.95,4.01 (each 1H, d, J=13.2 Hz, SOCH₂), 4.59 (1H, m, H₄), 4.84 (2H, m, CO₂CH₂), 5.37 (2H, m, CH₂ ═CH), 6.0 (1H, m, CH₂ ═CH), 6.47 (1H, m, NH),6.95 (2H, m, 4-FPh-H), 7.10 (2H, m, 4-FPh-H), 7.36 (2H, d, J=8 Hz, 4-CO₂allylPh-H), 8.09 (2H, d, J=8 Hz, 4-CO₂ allylPh-H). Found: C, 63.3; H,6.2; N, 5.4%. C₂₈ H₃₃ FN₂ O₅ S requires: C, 63.6; H, 6.3; N, 5.3%

EXAMPLE 165N-(6-{4-Fluorophenyl}hexyl)-4-(4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2)

Colourless solid, m.p. 115-117° C., 53% yield. ¹ H NMR δ (CDCl₃)1.30-1.60 (8H, m, 4xCH₂), 2.56 (2H, t, J=7.6 Hz, CH₂ Ph), 2.91, 2.95(1H, dd, J=2.4, 15.2 Hz, H₃), 3.27 (3H, m, NHCH₂, H₃), 3.94, 4.22 (each1H, d, J=17.2 Hz, NCH₂), 4.04, 4.18 (each 1H, d, J=12.8 Hz, SOCH₂), 4.65(1H, m, H₄), 4.84 (2H, m, CO₂ CH₂), 5.37 (2H, m, CH₂ ═CH), 6.0 (1H, m,CH₂ ═CH), 6.95 (3H, m, 4-FPh-H, NH),), 7.10 (2H, m, 4-FPh-H), 7.36 (2H,m, 4-CO₂ allylPh-H), 8.09 (2H, m, 4-CO₂ allylPh-H), ν _(c)═o 1795 cm⁻¹.Found: C, 63.5; H, 6.2; N, 5.4%. C₂₈ H₃₃ FN₂ O₅ S requires: C, 63.6; H,6.3; N, 5.3%

EXAMPLE 166N-(6-{-4-Fluorophenyl}hexyl)-4-(4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2)

A solution ofN-(6-{4-fluorophenyl}hexyl)-4-(4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(diastereoisomer 2) (0.35 g, 0.662 mmoles), triphenylphosphine (0.18 g,0.686 mmoles) and tetrakis(triphenylphospine)palladium(0) (22 mg) wastreated with a solution of pyrollidine (0.048 g, 0.675 mmoles) in drydichloromethane (1 ml). The reaction mixture was stirred for 22 h.Purification by column chromatography eluted with CH₂ Cl₂, 1:1 CH₂ Cl₂:acetone, 50:50:1 CH₂ Cl₂ :acetone:glacial acetic acid and washing withdichloromethane and ether gave the product as a colourless solid, m.p.185-186° C. (67% yield). ¹ H NMR δ (DMSO) 1.26 (4H, m, 2xCH₂), 1.38 (2H,m, CH₂), 1.50 (2H, m, CH₂), 2.96, 2.99 (1H, dd, J=2, 15.2 Hz, H₃), 3.06(2H, m, NHCH₂), 3.84, 4.09 (each 1H, d, J=17.2 Hz, NCH₂), 4.13, 4.31(each 1H, d, J=12.8 Hz, SOCH₂), 4.84 (1H, m, H₄), 7.05 (2H, m, 4-FPh-H),7.19 (2H, m, 4-FPh-H), 7.47 (2H, d, J=8 Hz, 4-CO₂ allylPh-H), 7.93 (2H,d, J=8 Hz, 4-CO₂ allylPh-H), 8.10 (1H, m, NH), 13 (1H, bs, CO₂ H).Found: C, 60.9; H, 5.9; N, 5.7%. C₂₅ H₂₉ FN₂ O₅ S.0.136H₂ O requires: C,61.2; H, 6.0; N, 5.7%

EXAMPLE 167N-(6-{4-Fluorophenyl}hexyl)-4-(4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2)

To a solution ofN-(6-{4-fluorophenyl}hexyl)-4-(4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(0.3 g, 0.6 mmol) in N-methyl pyrrolidin-2-one (4 ml) was addedanhydrous potassium carbonate (0.7 g, 5 mmol) and 2-iodopropane (0.9 g,5 mmol). The mixture was stirred for 18 h at room temperature, treatedwith aqueous brine and extracted with ethyl acetate. The organic extractwas washed with water, dried (MgSO₄) and evaporated. The residue waspurified by flash chromatography using a) ethyl acetate and b) ethylacetate:methanol (95:5) as the eluting solvents. Evaporation of theappropriate fractions gave the tiltle compound as a white powder (0.3 g,75%), mp 119° C.

¹ H NMR δ (CDCl₃) 1.33-1.41 (10H, m), 1.45-1.58 (4H, m), 2.56 (2H, t,J=7.5 Hz), 2.92 (1H, dd, J=2.5, 15.4 Hz), 3.15-3.40 (3H, m), 3.93 and4.24 (each 1H, d, J=18 Hz), 4.30 and 4.22 (each 1H, d, J=15 Hz), 4.69(1H, m), 5.25 (1H, m), 6.86-7.15 (5H, m), 7.35 (2H, m), 8.07 (2H, m).Found: C, 63.05; H, 6.46; N, 5.24. C₂₈ H₃₅ FN₂ O₅ S requires: C, 63.38;H, 6.65; N, 5.24%

The following compounds (Examples 168, 169) were prepared in ananalogous manner:

EXAMPLE 168N-(6-{4-Fluorophenyl}hexyl)-4-(4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2)

Cream solid, m.p. 113° C., 68% yield. ¹ H NMR δ (CDCl₃) 1.03 (3H, t,J=7.4 Hz, CH₃), 1.30-1.60 (8H, m, 4xCH₂), 1.80 (2H, m, CH₂ CH₃) 2.56(2H, t, J=7.6 Hz, CH₂ Ph), 2.90, 2.94 (1H, dd, J=2.4, 15.6 Hz, H₃), 3.22(3H, m, NHCH₂, H₃), 3.94, 4.22 (each 1H, d, J=17.2 Hz, NCH₂), 4.04, 4.18(each 1H, d, J=12.8 Hz, SOCH₂), 4.30 (2H, t, J=6.6 Hz, CO₂ CH₂), 4.65(1H, m, H₄), 6.95 (3H, m, 4-FPh-H, NH),), 7.10 (2H, m, 4-FPh-H), 7.36(2H, m, 4-CO₂ propylPh-H), 8.07 (2H, m, 4-CO₂ propylPh-H). ν _(c)═o 1795cm ⁻¹. Found: C, 62.4; H, 6.4; N, 5.3%. C₂₈ H₃₅ FN₂ O₅ S.1% H₂ Orequires: C, 62.7; H, 6.7; N, 5.2%

EXAMPLE 169N-[6-(4-Fluorophenyl)hexyl]-[4-(4-ethyloxycarbonylbenzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide(Diastereoisomer 2)

Off-white solid, 82% yield, m.p. 130-31° C. ¹ H NMR δ (CDCl₃)1.3-1.6(11H, m), 2.55(2H, t), 2.91(1H, dd), 3.25(1H, dd), 3.27(2H, m),3.94 & 4.23(each 1H, d, J=20 Hz), 4.17 & 4.02(each 1H, d=12.5 Hz),4.39(2H, q), 4.65(1H, dd), 7.01(5H, m), 7.35 & 8.07(each 2H, d, J=8.27Hz).

Found: C, 62.6; H, 6.3; N, 5.4% C₂₉ H₃₃ FN₂ O₅ S requires: C, 62.8; H,6.4; N, 5.4%

EXAMPLE 170N-(6-[4-Fluorophenyl]hex-1-yl)-4-carboxybenzylthio)-2-oxoazetidin-1-ylacetamide

Treatment ofN-(6-[4-fluorophenyl]hex-1-yl)-4-allyloxycarbonylbenzylthio)-2-oxoazetidin-1-ylacetamide under the conditions described in Example 166 gave the titlecompound as a colourless oil, 62% yield. ¹ H NMR δ 1.24 (4H, bm),1.41-1.51 (4H, bm), 2.50 (3H, t, J=7.4 Hz), 2.87-2.93 (1H, bdd),3.09-3.47 (4H, m) 3.6-3.80 (3H, m), 4.86 (1H, bm), 6.75 (1H, bm),6.86-6.96 (2H, m), 7.03-7.09 (2H, m), 7.26 (2H,m), 7.97 (2H,m)

EXAMPLE 171N-(6-[4-Fluorophenyl]hex-1-yl)-(4-methoxycarbonylbenzylthio)-2-oxoazetidin-1-ylacetamide

N-(6-[4-fluorophenyl]hex-1-yl)-4-carboxybenzylthio)-2-oxoazetidin-1-ylacetamide (1 g, 2.1 mmol) was dissolved in dry dichloromethane (5 ml)and the solution treated with a solution of trimethylsilyldiazomethane(6 ml of 2M hexane solution) over a period of 3 hours with stirring.Solvent was removed and the residue was chromatographed on silica usingdichloromethane:methanol (9:1) as the eluting solvent. Evaporation ofthe appropriate fractions gave the title compound as an oil (0.27 g, 26%yield).

¹ H NMR δ 1.32 (4H, bm), 1.4-1.7 (4H, bm), 2.56 (3H, t, J=7.4 Hz), 2.9(1H, dd, J=2.5, 15.3 Hz), 3.15-3.35 (3H, m), 3.4-4.0 (7H, m), 4.86 (1H,m), 5.99 (1H, bm), 6.90-6.98 (2H, m), 7.07-7.13 (2H, m), 7.40 (2H, m),7.97 (2H, m)

EXAMPLE 172N-[6-(4-Fluorophenyl)hexyl]-[4-(4-methyloxycarbonylbenzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide(Diastereoisomer 2)

Treatment ofN-(6-[4-fluorophenyl]hex-1-yl)-(4-methoxycarbonylbenzylthio)-2-oxoazetidin-1-ylacetamide with mCPBA as described in Examples 2 and 3 gace the titlecompound as a waxy solid, 26% yield. ¹ H NMR δ 1.34 (3H, bm) 1.4-1.7(4H, m), 155-1.70 (4H, m), 2.50 (3H, t), 2.95 (1H, dd), 3.15-3.3 (3H,m),3.9-4.3 (7H, m), 4.6 (1H, m), 6.94 (2H, t), 7.12 (2H, t), 7.36 (2H, d).8.06 (2H, d), 8.06 (2H, d). ν _(c)═o 1795 cm⁻¹. Found: C, 61.72; H,6.17; N, 5.5%. C₂₆ H₃₁ FN₂ O₅ S requires: C, 62.13; H, 6.22; N, 5.6%

EXAMPLE 173N-(6-{4-Chlorophenyl}hexyl)-4-(4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2).

Treatment ofN-(6-{-4-chlorophenyl}hexyl)-4-(4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2) (Example 130) with isopropyl iodide using the methoddescribed in Example 169 gave the title compound as white crystals, 78%yield, m.p. 114.5° C. Found: C, 61.45; H, 6.35; N, 5.26%. C₂₈ H₃₅ ClN₂O₅ S requires: C, 61.47; H, 6.45; N, 5.12%.

EXAMPLE 174N-(6-{4-Chlorophenyl}hexyl)-4-(4-propyloxycarbonylbenzlsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2).

Treatment ofN-(6-{4-chlorophenyl}hexyl)-4-(4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2) (Example 130) with n-propyl iodide using the methoddescribed in Example 169 gave the title compound as a white powder, 69%yield, m.p. 104° C. ¹ H NMR δ (CDCl₃) 1.03 (3H, t, J=7.4 Hz), 1.36 (4H,m), 1.55 (4H, m), 1.81 (2H, m), 2.56 (2H, t, J=7.9 Hz), 2.89 (1H, dd,J=2.5, 15.3 Hz), 3.23 (3H, m), 3.90 and 4.16 (each 1H, d, J=17.1 Hz),4.00 and 4.27 (each 1H, d, J=12.9 Hz), 4.32 (t, J=7.4 Hz), 4.63 (1H, m),7.01 (1H, bm), 7.06 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz), 7.34 (2H,d, J=8.3 Hz), 8.05 (2H, d, J=8.3 Hz).

EXAMPLE 175N-(6-{4-Chlorophenyl}hexyl)-4-(4-ethyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2).

Treatment ofN-(6-{4-chlorophenyl}hexyl)-4-(4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereoisomer 2) (Example 130) with ethyl iodide using the methoddescribed in Example 169 gave the title compound as a white powder, 70%yield, m.p. 124° C. 1.33 (4H, m), 1.40 (3H, t, J=7.1 Hz), 1.55 (4H, m),2.56 (t, J=7.4 Hz), 2.88 (1H, dd, J=<2, 17.7 Hz), 3.19-3.27 (3H, m),3.90 and 4.19 (each 1H, d, J=17.1 Hz), 4.01 and 4.16 (each 1H, d, J=12.9Hz), 4.35 (2H, q, J=7.2 Hz, 7.01 (1H, bm), 7.06 (2H, d, J=8.4 Hz), 7.24(2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.3 Hz), 8.05 (2H, d, J=8.3 Hz).

EXAMPLE 176N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(allyloxycarbonylmethyl)benzyl)thio-2-oxo-azetidin-1-yl]-acetamide

Treatment of 4-(4-(allyloxycarbonylmethyl)benzylthio)azetidin-2-one withN-(6-(-4-fluorophenyl)hexyl)-1-bromoacetamide by the method described inExample 85a gave the title compound as a olourless oil, 16% yield. ¹ HNMR δ (CDCl₃) 1.30-1.60(8H, m), 2.56(2H, t), 3.00-2.95(1H, dd),2.97&3.57(each 1H, dd), 3.23(1H, m), 3.42(1H, dd), 3.65(2H, s), 3.77(2H,q), 4.59(2H, m), 4.88 (1H, dd), 5.23-5.32(2H, m), 5.9(1H, m), 6.1 (1H,t), 6.9-7.30 (8H, m)

Treatment ofN-(6-(4-fluorophenyl)hexyl)-4-(4-(allyloxycarbonylmethyl)benzylthio-2-oxoazetidin-1-yl)acetamidewith mCPBA followed by recrystallisation as described for Example 2 and3 gave the compounds described in Examples 178 and 179.

EXAMPLE 177 N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(allyloxycarbonylmethyl)benzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide (Diastereomer 1)

White crystalline solid, 16% yield, m.p.132-33° C.

Found: C, 63.3; H, 6.3; N, 5.0%. C₂₉ H₃₅ FN₂ O₅ S0.5H₂ O requires: C,63.2; H, 6.6; N, 5.1%

EXAMPLE 178 N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(allyloxycarbonylmethyl)benzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide (Diastereomer 2)

White crystalline solid, 56% yield, m.p.106-9° C.

Found: C, 64.2; H, 6.4; N, 5.1%. C₂₉ H₃₅ FN₂ O₅ S requires: C, 64.2; H,6.4; N, 5.2%

EXAMPLE 179 N-[6-(4-Fluorophenyl)hexyl]-[4-(4-carboxymethyl)benzyl)thio-2-oxo-azetidin-1-yl]-acetamide

Treatment ofN-[6-(4-fluorophenyl)hexyl]-[4-(4-(allyloxycarbonylmethyl)-benzyl)thio-2-oxo-azetidin-1-yl]-acetamideunder the conditions described for Example 166 gave the title compoundas a white solid, 87% yield, m.p. ¹ H NMR δ (CDCl₃) 1.21 (4H, m), 1.45(2H, m), 1.58 (4H, m), 2.56 (2H, t, J=7.6 Hz), 2.84 and 3.47 (each 1H,d, J=16.9 Hz), 2.90 (1H, dd, J=<2, 16.6 Hz), 3.14 (2H, m), 3.39 (1H, dd,J=5.3, 15.1 Hz), 3.64 (2H, s), 3.69 (2H, dd, J=7.7, 14.3 Hz), 4.86 (1H,m), 6.29 (1H, bm), 6.91-7.26 (8H, m).

EXAMPLE 180 N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(carboxymethyl)benzylsulphinyl-2-oxo-azetidin-1-yl]-acetamide (Diastereomer 1)

Ozonised oxygen was bubbled through a solution ofN-[6-(4-fluorophenyl)hexyl]-[4-(4-(carboxymethyl)benzyl)thio-2-oxo-azetidin-1-yl]-acetamide(1.5 g, 3 mmol) in dichloromethane (100 ml) at -78° C. until a pale bluecolour persisted. Nitrogen was purged through the reaction, the mixtureallowed to reach room temperature and evaporated to dryness. The residuewas crystallised from ethyl acetate to give the title compound (0.49 g,33%) m.p. 160-61° C. ¹ H NMR δ (DMSO-d₆) 1.26 (4H, m), 1.38 (2H, m),1.53 (2H, m), 2.54 (2H, t, J=7.6 Hz), 3.04 (3H, m), 3.14 (1H, dd,J=1.6,>12 Hz), 3.57 (2H, s), 3.57 and 4.00 (each 1H, d, J=21.6 Hz), 3.80and 4.10 (each 1H, J=13.2 Hz), 4.89 (1H, m), 7.05-7.26 (8H, m), 7.98(1H, bm), 12.3 (1H, bs).

EXAMPLE 181N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(carboxymethyl)benzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide(Diastereomer 2)

Evaporation of the filtrate from the above crystallisation gavediastereomer 2 contaminated with diastereomer 1 (ratio 65:35) (0.31 g,20%) m.p. 125-129° C. ¹ H NMR δ (DMSO-d₆) 1.26 (4H, m), 1.37 (2H, m),1.51 (2H, m), 2.55 (2H, m), 2.91 (1H, dd, J=2.4, 15.2 Hz), 3.06 (2H, m),3.29 (1H, m), 3.57 (2H, s), 3.99-4.21 (4H, m), 4.82 (1H, m), 7.05-7.29(8H, m), 8.13 (1H, bm), 12.32 (1H, bs).

EXAMPLE 182N-2,4-Dichlorobenzyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Treatment of (4-benzylthio-2-oxoazetidin-1-yl)acetic acid with2,4-dichlorobenzylamine under the conditions described for Example 86gave the title compound as a colourless solid, m.p. 132-133° C., 72%yield. ¹ H nmr δ (CDCl₃) 2.93, 2.97 (1H, dd, J=2.4, 15.4 Hz, H₃), 3.36,3.39 (1H, dd, J=5.2, 15.4 Hz, H₃), 3.56, 3.70 (each 1H, d, J=16.9 Hz,NCH₂), 3.76 (2H, s, SCH₂), 4.47 (2H, m, NHCH₂), 4.80 (1H, m, H₄), 6.5(1H, m, NH), 7.20-7.34 (7H, m, Ph-H, 2,4-diClPh-H), 7.38 (1H, d, J=2 Hz,2,4-diClPh-H). ν _(c)═o 1776 cm⁻¹. Found: C, 55.8; H, 4.5; N, 6.9%. C₁₉H₁₈ Cl₂ N₂ O₂ S requires: C, 55.8; H, 4.4; N, 6.8%

Treatment ofN-2,4-dichlorobenzyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide withmCPBA followed by recrystallisation as described in Examples 2 and 3gave the compounds described in Examples 183 and 184. Treatment ofN-2,4-dichlorobenzyl-(4-benzylsulfinyl-2-oxoazetidin-1-yl)acetamide withmCPBA gave Example 185.

EXAMPLE 183N-2,4-Dichlorobenzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereomer 1)

Colourless solid, m.p. 224-226° C., 16% yield. ¹ H nmr δ (DMSO) 3.03,3.07 (1H, dd, J=4.8, 14.8 Hz, H₃), 3.15, 3.18 (1H, dd, J=1.6, 14.8 Hz,H₃), 3.78, 4.16 (each 1H, d, J=16.8 Hz, NCH₂), 3.85, 4.14 (each 1H, d,J=12.8 Hz, SOCH₂), 4.33 (2H, d, J=5.6 Hz, NHCH₂), 4.93 (1H, m, H₄),7.32-7.42 (7H, m, Ph-H, 2,4-diClPh-H), 7.61 (1H, d, J=2 Hz,2,4-diClPh-H), 8.62 (1H, m, NH). Found: C, 51.7; H, 4.2; N,6.4%. C₁₉ H₁₈Cl₂ N₂ O₃ S requires: C, 53.7; H, 4.3; N, 6.6%

EXAMPLE 184N-2,4-Dichlorobenzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereomer 2

Colourless solid, m.p. 162-163° C., 45% yield. ¹ H nmr δ (DMSO) 2.91,2.95 (1H, dd, J=2.2, 15.4 Hz, H₃), 3.30 (1H, m, H₃), 3.97, 4.21 (each1H, d, J=17.2 Hz, NCH₂), 4.05, 4.20 (each 1H, d, J=12.8 Hz, SOCH₂), 4.34(2H, d, J=5.8 Hz, NHCH₂), 4.83 (1H, m, H₄), 7.32-7.42 (7H, m, Ph-H,2,4-diClPh-H), 7.60 (1H, d, J=2 Hz, 2,4-diClPh-H), 8.72 (1H, m, NH). ν_(c)═o 1793 cm⁻¹. Found: C, 53.5; H, 4.4; N, 6.6%. C₁₉ H₁₈ Cl₂ N₂ O₃ Srequires: C, 53.7; H, 4.3; N, 6.6%

EXAMPLE 185N-2,4-Dichlorobenzyl-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide

Colourless solid, m.p. 163-164° C., 77% yield. ¹ H nmr δ (DMSO) 3.08(1H, m, H₃), 3.30 (1H, m, H₃), 3.77, 4.19 (each 1H, d, J=17.2 Hz, NCH₂),4.34 (2H, m, NHCH₂), 4.66, 4.77 (each 1H, d, J=13.4 Hz, SO₂ CH₂), 5.09(1H, m, H₄), 7.38 (7H, m, Ph-H, 2,4-diClPh-H), 7.62 (1H, m,2,4-diClPh-H), 8.67 (1H, m, NH). ν _(c)═o 1796 cm⁻¹. Found: C, 51.5; H,4.1; N, 6.3%. C₁₉ H₁₈ Cl₂ N₂ O₄ S requires: C, 51.7; H, 4.1; N, 6.4%

EXAMPLE 186N-3,4-Dichlorobenzyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide

Treatment of (4-benzylthio-2-oxoazetidin-1-yl)acetic acid with3,4-dichlorobenzylamine under the conditions described for Example 86gave the title compound as a c olourless solid, m.p. 90-91° C., 68%yield. ¹ H nmr δ (CDCl₃) 2.94, 2.98 (1H, dd, J=2.4, 15.6 Hz, H₃), 3.36,3.39 (1H, dd, J=5.2, 15.6 Hz, H₃), 3.62, 3.70 (each 1H, d, J=16.8 Hz,NCH₂), 3.79 (2H, s, SCH₂), 4.38 (2H, m, NHCH₂), 4.80 (1H, m, H₄), 6.5(1H, m, NH), 7.12 (1H, m, 3,4-diClPh-H), 7.26-7.40 (7H, m, Ph-H,3,4-diClPh-H). ν _(c)═o 1778 cm⁻¹. Found: C, 55.8; H, 4.5; N, 6.9%. C₁₉H₁₈ Cl₂ N₂ O₂ S requires: C, 55.8; H, 4.4; N, 6.8%

Treatment ofN-3,4-dichlorobenzyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide withmCPBA followed by recrystallisation as described in Examples 2 and 3gave the compounds described in Examples 187 and 188. Treatment ofN-3,4-dichlorobenzyl-(4-benzylsulfinyl-2-oxoazetidin-1-yl)acetamide withmCPBA gave Example 189.

EXAMPLE 187N-3,4-Dichlorobenzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereomer 1)

Colourless solid, m.p. 213-214° C., 14% yield. ¹ H nmr δ (DMSO) 3.03,3.06 (1H, dd, J=4.4, 14.8 Hz, H₃), 3.15, 3.18 (1H, dd, J=2, 14.8 Hz,H₃), 3.78, 4.14 (each 1H, d, J=17.2 Hz, NCH₂), 3.85, 4.14 (each 1H, d,J=12.8 Hz, SOCH₂), 4.29 (2H, d, J=6 Hz, NHCH₂), 4.93 (1H, m, H₄), 7.25(1H, m, 3,4-diClPh-H), 7.31-7.40 (5H, m, Ph-H), 7.52-7.56 (2H, m,3,4-diClPh-H), 8.62 (1H, m, NH). Found: C, 53.0; H, 4.3; N, 6.5%. C₁₉H₁₈ Cl₂ N₂ O₃ S requires: C, 53.7; H, 4.3; N, 6.6%

EXAMPLE 188N-3,4-Dichlorobenzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide(Diastereomer 2)

Colourless solid, m.p. 155-156° C., 33% yield. ¹ H nmr δ (DMSO) 2.91,2.95 (1H, dd, J=2.2, 15.3 Hz, H₃), 3.30 (1H, m, H₃), 3.96, 4.18 (each1H, d, J=17.2 Hz, NCH₂), 4.05, 4.20 (each 1H, d, J=12.8 Hz, SOCH₂), 4.31(2H, d, J=5.9 Hz, NHCH₂), 4.83 (1H, m, H₄), 7.27 (1H, m, 3,4-diClPh-H),7.31-7.37 (5H, m, Ph-H), 7.54-7.57 (2H, m, 3,4-diClPh-H), 8.72 (1H, m,NH). ν _(c)═o 1795 cm⁻¹. Found: C, 53.7; H, 4.3; N, 6.5%. C₁₉ H₁₈ Cl₂ N₂O₃ S requires: C, 53.7; H, 4.3; N, 6.6%

EXAMPLE 189N-3,4-Dichlorobenzyl-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide

Colourless solid, m.p. 173-174° C., 86% yield. ¹ H nmr δ (DMSO) 3.08(1H, m, H₃), 3.30 (1H, m, H₃), 3.76, 4.18 (each 1H, d, J=17.2 Hz, NCH₂),4.31 (2H, d, J=5.9 Hz, NHCH₂), 4.66, 4.77 (each 1H, d, J=13.4 Hz, SO₂CH₂), 5.09 (1H, m, H₄), 7.27 (1H, m, 3,4-diClPh-H), 7.38 (5H, s, Ph-H),7.53-7.59 (2H, m, 3,4-diClPh-H), 8.66 (1H, m, NH). Found: C, 51.6; H,4.2; N, 6.4%. C₁₉ H₁₈ Cl₂ N₂ O₄ S requires: C, 51.7; H, 4.1; N, 6.4%

EXAMPLE 190(3S,4R)-N-(6-{4-Fluorophenyl}hexyl)-(3-chloro-4-benzylthio-2-oxoazetidin-1-yl)acetamide

a. (3S,4R)-(4-Benzylthio-3-chloro-2-oxoaxetidin-1-yl)acetic acid

A suspension of methyl[(3S,4R)-4-benzylthio-3-chloro-2-oxoxazetidin-1-yl)acetate (2.87 g,0.00957 mol) (Example 305) in methanol (50 ml) was cooled to 10° C. and1N aq. sodium hydroxide (9.6 ml) was added over 40 minute. The coolingbath was removed and reaction was stirred for 30 min, evaporated toremove methanol, diluted with water and washed with ethyl acetate. Theaqueous layer was acidified with dilute hydrochloric acid and extractedwith ethyl acetate (x2). The organic extracts were combined and washedwith brine, dried (MgSO₄), evaporated to an oil. Precipitation fromether-pet. ether gave the product as colourless solid, 1.15 g (42%, m.p.132-134° C.).

b.(3S,4R)-N-(6-{4-Fluorophenyl}hexyl)-(3-chloro-4-benzylthio-2-oxoazetidin-1-yl)acetamide

Treatment of (3S,4R)-(4-benzylthio-3-chloro-2-oxoazetidin-1-yl)aceticacid with 6-(4-fluorophenyl)hexylamine under the conditions describedfor Example 86 gave the title compound as a colourless oil, 85% yield. ¹H NMR δ (CDCl₃) 1.3-1.6 (8H, m, 4xCH₂), 2.56 (2H, t, J=7.6 Hz, CH₂ Ph),3.22 (2H, m, NHCH₂), 3.51, 3.81 (each 1H, d, J=16.5 Hz, NCH₂), 3.83 (2H,s, SCH₂), 4.58 (1H, d, J=1.7 Hz, H₄), 4.79 (1H, d, J=1.7 Hz, H₃), 5.80(1H, m, NH), 6.95 (2H, m, 4-FPh--H), (2H, m, 4-FPh--H), 7.30 (5H, m.Ph--H)

Treatment of(3S,4R)-N-(6-{4-fluorophenyl}hexyl)-(3-chloro-4-benzylthio-2-oxoazetidin-1-yl)acetamidewith mCPBA under the conditions described for Examples 2 and 3 gave thecompounds described in Examples 191 and 192.

EXAMPLE 191(SR,3S,4R)-N-(6-{4-Fluorophenyl}hexyl)-3-chloro-4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

Colourless solid, m.p. 135-136° C., 18% yield. ¹ H NMR δ (CDCl₃) 1.3-1.6(8H, m 4xCH₂), 2.56 (2H, t, J=7.8 Hz, CH₂ Ph), 3.22 (2H, m, NHCH₂), 3.80, 4.13 (each 1H, d, J=17.2 Hz, NCH₂), 4.08, 4.23 (each 1H, d, J=13.2 Hz,SOCH₂), 4.67 (1H, d, J=1.6 Hz, H₄), 5.38 (1H, d, J=1.6 Hz, H₃), 6.47(1H, m, NH), 6.95 (2H, m, 4-FPh--H), 7.10 (2H, m, 4-FPh--H), 7.39 (5H,m. Ph--H). υ_(C)═O 1808 cm⁻¹. [α]_(D) at 25° C.=-117.4 (0.973% w/vCHCl₃). Found: C, 60.1; H, 5.8; N, 5.9%. C₂₄ H₂₈ ClFN₂ O₃ S requires: C,60.2; H, 5.9; N, 5.9%

EXAMPLE 192(SS,3S,4R)-N-(6-{4-Fluorophenyl}hexyl)-(3-chloro-4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide

Colourless solid, m.p. 87-89° C., 52% yield. ¹ H NMR δ (CDCl₃) 1.3-1.6(8H, m, 4xCH₂), 2.56 (2H, t, J=7.6 Hz, CH₂ Ph), 3.26 (2H, m, NHCH₂),3.92, 4.28 (each 1H, d, J=17.2 Hz, NCH₂), 4.10, 4.18 (each 1H, d, J=13.2Hz, SOCH₂), 4.65 (1H, d, J=2 Hz, H₄), 4.72 (1H, d, J=2 Hz, H₃), 6.95(2H, m, 4-FPh--H), 7.09 (1H, m, NH), 7.10 (2H, m, 4-FPh--H), 7.39 (5H,m. Ph--H). υ_(C)═O 1809 cm⁻¹. [α]_(D) at 25° C.=+75.3 (0.908% w/vCHCl₃). Found: C, 60.2; H, 5.9; N, 5.9%. C₂₄ H₂₈ ClFN₂ O₃ S requires: C,60.2; H, 5.9; N, 5.9%

EXAMPLE 193N-(6-(4-Fluorophenyl)hexyl)-(3S,4R)-4-benzylthio-3-((R)-hydroxyethyl)-2-oxoazetidin-1-ylacetamide

(a)(3S,4R)-4-Benzylthio-3-((R)-(t-butyldimethylsilyloxy)ethyl)-2-azetidinone

Treatment of(3R,4R)-4-acetoxy-3-((R)-(t-butyldimethylsilyloxy)ethyl)-2-azetidinonewith sodium benzylthiolate as described in Example 1a gave the titlecompound as a waxy solid, m.p. 69-70° C., 95% yield. ¹ H NMR δ (CDCl₃)0.01 (6H, 2xs, SiCH₃), 0.83 (9H, s, tBu--H), 1.13 (3H, d, J=6 Hz, CH₃),3.14 (1H, m, H₃), 3.82 (2H, s, SCH₂), 4.15 (1H, m, CH₃ CH), 4.75 (1H, d,J=2 Hz, H₄), 5.36 (1H, br s, NH), 7.28 (5H, m, Ph--H)

(b)N-(6-(4-Fluorophenyl)hexyl)-(3S,4R)-4-benzylthio-3-((R)-(t-butyldimethylsilyloxy)ethyl)-2-oxoazetidin-1-ylacetamide

Treatment of(3S,4R)-4-benzylthio-3-((R)-(t-butyldimethylsilyloxy)ethyl)-2-azetidinonewith N-(6-(4-fluorophenyl)hexyl)-1-bromo0acetamide as described inExample 85 gave the title compound as a colourless oil, 54% yield. ¹ HNMR δ (CDCl₃) 0.01 (6H, 2xs, SiCH₃), 0.82 (9H, s, tBu--H), 1.07 (3H, d,J=6 Hz, CH₃), 1.3-1.6 (8H, m, 4xCH₂) 2.56 (2H, t, J=8 Hz, CH₂ Ar), 3.14(1H, m, H₃), 3.25 (2H, m, NHCH₂), 3.54, 3.81 (2H, 2xd, J=17 Hz, NCH₂),3.82 (2H, s, SCH₂), 4.20 (1H, m, CH₃ CH), 4.75 (1H, d, J=2 Hz, H₄), 6.40(1H, br t, NH), 6.95, 710 (4H, 2xm, FPh--H), 7.30 (5H, m, Ph--H)

(c)N-(6-(4-Fluorophenyl)hexyl)-(3S,4R)-4-benzylthio-3-((R)-hydroxyethyl)-2-oxoazetidin-1-ylacetamide

N-(6-(4-Fluorophenyl)hexyl)-(3S,4R)-4-benzylthio-3-((R)-(t-butyldimethylsilyloxy)ethyl)-2-oxoazetidin-1-ylacetamide(2.68 g; 4.57 mmoles) and glacial acetic acid (0.4 ml) were dissolved indry THF (50 ml) and a molar solution of tetrabutylammonium fluoride inTHF (6.9 ml; 6.9 mmoles) added. The solution was refluxed for 24 hours,more TBAF (2 ml; 2 mmoles) added and refluxing continued for a further24 hours. The solution was poured into water (50 ml) and ethyl acetate(50 ml), separated and the organics washed with water, brine, dried overmagnesiunm sulphate and evaporated to a brown solid which wasrecrystallised from ethyl acetate/ether to give a cream solid (1.69 g)m.p. 102-4° C., 78% yield. ¹ H NMR δ (CDCl₃) 1.2-1.7 (11 H, m, 4xCH₂+CH₃), 2.34 (1H, br s, OH) 2.56 (2H, t, J=8 Hz, CH₂ Ar), 3.20 (3H, m,NHCH₂ +H₃), 3.31, 3.92 (2H, 2xd, J=17 Hz, NCH₂), 3.79 (2H, s, SCH₂),4.34 (1H, m, CH₃ CH), 4.76 (1H, m, H₄), 6.64 (1H, br t, NH), 6.95, 7.09(4H, 2xm, FPh--H), 7.25 (5H, m, Ph--H)

EXAMPLE 194N-(6-(4-Fluorophenyl)hexyl)-(3S,4R)-4-benzylsulphinyl-3-((R)-hydroxyethyl)-2-oxoazetidin-1-ylacetamide(Diastereomer 2).

Treatment ofN-(6-(4-fluorophenyl)hexyl)-(3S,4R)-4-benzylthio-3-((R)-hydroxyethyl)-2-oxoazetidin-1-ylacetamidewith mCPBA as described for Example 2 gave the title compound as acolourless solid, m.p. 164-7° C., 17% yield. ¹ H NMR δ (CDCl₃) 1.3-1.7(11H, m, 4xCH₂ +CH₃), 2.45 (1H, m, OH) 2.56 (2H, t, J=8 Hz, CH₂ Ar),3.25 (2H, m, NHCH₂), 3.40 (1H, m, H₃), 3.8-4.25 (4H, m, NCH₂ +SOCH₂),4.33 (1H, m, CH₃ CH), 4.69 (1H, m, H₄), 6.95, 7.09 (4H, 2xm, FPh--H),7.2-7.5 (6H, m, Ph--H+NH). υ_(C)═O 1782 cm⁻¹. Found: C, 63.6; H, 6.7; N,5.8%. C₂₆ H₃₃ FN₂ O₄ S requires: C, 63.9; H, 6.8; N, 5.7%

EXAMPLE 201N-(6-phenylhexyl)-(4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl)acetamide

a. Methyl-(4-methoxyphenylthio-2-oxoazetidin-1-yl)acetate

To a solution of 4-(4-methoxyphenylthio)azetidin-2-one (H. Gu et al., J.Org. Chem., 1990, 55, 5655) (11.6 g, 55 mmol), methyl bromoacetate (9.2g, 60 mmol) and tetrabutylammonium bromide (1.8 g, 0.56 mmol) in dry THF(300 ml) was added powdered potassium hydroxide (3.4 g, 60 mmol). Theresulting mixture was stirred for two hours at room temperature beforewater (100 ml) was added. The solution was extracted with ethyl acetate(3×150 ml portions) and the combined extracts dried (MgSO₄) andevaporated. The residue was purified by flash chromatography on silicagel eluted with ethylacetate/hexane (1:1→2:1) to give the product as asolid mp 101-103° C. 58% yield 1H NMR δ (CDCl₃) 2.80 (1H, dd, J=2.2, 15Hz H_(3a)), 3.34 (1H, dd, J=5, 15 Hz, H_(3b)), 3.72 (3H, s, OCH₃), 3.77,4.29 (each 1H, d, J=18.00 Hz, NCH₂), 3.80 (3H, s, SCH₃), 5.07 (1H, m,H₄), 6.87 (2H, d, J=10 Hz, 2.6 Ph--H), 7.35 (2H, d, J=10 Hz, 3, 5Ph--H).

b. (4-(4-Methoxyphenylthio)-2-oxoazetidin-1-yl)acetic acid

To a solution of methyl-(4-methoxyphenylthio-2-oxoazetidin-1-yl)acetate(5.2 g, 18 mmol) in methanol (80 ml) was added, dropwise at 0° C., asolution of 1 N sodium hydroxide (20 ml, 20 mmol). The reaction wasstirred for 1 hr and evaporated to dryness. Water (50 ml) was added andthe solution acidified to pH 3 with dilute hydrochloric acid andextracted with ethyl acetate (3×100 ml). The combined extracts weredried (MgSO₄), evaporated and the residue purified by recrystallisation(hexane/ether) to give the product as a white solid, mp 78-79° C., 79%yield 1H NMR δ (CDCl₃) 2.80 (1H, dd, J=1.9, 15 Hz, H_(3a)), 3.34 (1H,dd, J=5, 15 Hz, H_(3b)), 3.80 (3H, s, OCH₃), 3.82, 4.30 (each 1H, d,J=18.00 Hz, NCH₂), 5.06 (1H, m, H₄), 6.40 (1H, bs, NH), 6.87 (2H, d,J=6.8 Hz, 2, 6 Ph--H), 7.35 (2H, d, J=6.8 Hz, 3, 5 Ph--H).

c.N-(6-phenylhexyl)-(4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl)acetamide

A solution of 6-phenylhexylamine (Morse M. A. et al., Cancer Research,1991, 1846), (1.4 g, 8 mmol) in DMF (50 ml) was added to DCC (1.6 g, 8mmol), hydroxybenzotriazole (1.0 g, 8 mmol) and(4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl)acetic acid (2.1 g, 8 mmol)and the mixture stirred for 2 hours at room temperature. Ethyl acetate(250 ml) was added, the precipitate filtered, the filtrate washed withdil NaHCO₃, water (x2), dried (MgSO₄) and evaporated to an oil which waspurified by flash chromatography on silica gel using hexane/ethylacetate (1:3). Evaporation of the appropriate fractions gave the productas a colourless oil, 77% yield. ¹ H NMR δ (CDCl₃) 1.34-1.47 (10H, m,(CH₂)₅), 2.59 (2H, t, J=7.7 Hz, CH₂), 2.83 (1H, dd, J=2.2, 15 Hz,H_(3a)), 3.18-3.36 (3H, m, CH₂ H_(3b)), 3.78 (3H, s, OCH₃), 3.80, 3.99(each 1H, d, J=15 Hz, NCH₂), 4.95 (1H, m, H₄), 6.23 (1H, bt, NH), 6.87(2H, d, J=6.8 Hz, 2, 6 Ph--H), 7.14-7.39 (7H, m, 3, 5 Ph--H, Ph--H).

EXAMPLE 202 (4R,SR/4S,SS)N-(6-phenylhexyl)-(4-(4-methoxyphenyl)sulfinyl)-2-oxoazetidin-1-yl)acetamide

A solution ofN-(6-phenylhexyl)-(4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl)acetamide(2.5 g, 5.8 mmol) in dichloromethane (100 ml) was cooled to -70° C. anda solution of m-chloroperbenzoic acid (1.0 g, 6.4 mmol) indichloromethane (100 ml) added dropwise with stirring over 60 min. Aftera further 3 h at -60° C., the reaction mixture was shaken with a mixtureof saturated aqueous sodium sulphite and saturated sodium hydrogencarbonate. The organic layer was separated, washed with brine, dried(MgSO₄) and evaporated to a solid which was titurated with ether andfiltered. Two recrystallisations from ethyl acetate gave (R^(C) R^(S)/S^(C) S^(S))N-(6-phenylhexyl)-(4-(4-methoxyphenyl)sulfinyl)-2-oxoazetidin-1-ylacetamide (0.4 g, 14%) m.p. 123-125° C. Found: C, 64.9; H, 6.6; N, 6.3%;C₂₄ H₃₀ N₂ O₄ S requires: C, 65.1; H, 6.8; N, 6.3%

EXAMPLE 203(4R,SS/4S,SR)-N-(6-phenylhexyl)-(4-(4-methoxyphenyl)sulfinyl)-2-oxoazetidin-1-yl)acetamide

Evaporation of the filtrate gave a waxy solid which was further purifiedby chromatography on silica to give a gummy solid as a 9:1 mixture ofdiastereisomers, in favour of the title compound. Found: C, 64.0; H,6.8; N, 6.1%; C₂₄ H₃₀ N₂ O₄ S 0.4 EtOAc requires: C, 64.3; H, 7.0; N,5.9%

EXAMPLE 204

A solution ofN-(6-phenylhexyl)-(4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl)acetamide(2.1 g, 5 mmol) in dichloromethane (100 ml) was cooled to -70° C. and asolution of m-chloroperbenzoic acid (2.0 g, 11 mmol) in dichloromethane(100 ml) added dropwise with stirring over 60 min. After a further 2 hat 20° C., the reaction mixture was shaken with a mixture of saturatedaqueous sodium sulphite and saturated sodium hydrogen carbonate. Theorganic layer was separated, washed with brine, dried (MgSO₄) andevaporated to a solid which was recrystallised from ethyl acetate to awhite solid, 1.2 g (53% yield, m.p. 93-95° C. Found: C, 62.7; H, 6.6; N,6.2%; C₂₄ H₃₀ N₂ O₅ S requires: C, 62.9; H, 6.6; N, 6.1%

EXAMPLE 205N-(6-phenylhexyl)-(4-(3,4-dimethoxyphenylthio)-2-oxoazetidin-1-yl)acetamide

a. 4-(3,4-Dimethoxyphenylthio)azetidin-2-one

Sodium (0.9 g, 39 mmol) was dissolved in ethanol (150 ml) and3,4-dimethoxythiophenol (5.9 g, 35 mmol) added dropwise over 20 minuteskeeping the temperature between 20° C.-25° C. whilst bubbling nitrogenthrough the mixture. After 15 minutes, the reaction was cooled to 5° C.and a solution of 4-acetoxyazetidin-2-one (4.3 g, 33 mmol) in ethanol(50 ml) was added dropwise over 15 minutes whilst maintaining thetemperature at 5° C. The mixture was stirred at room temperature for 60minutes and evaporated to dryness under reduced pressure. Water (400 ml)was added, the mixture extracted with dichloromethane (2×300 ml), theextracts dried (MgSO₄) and evaporated under reduced pressure to an oil.The oil was cooled to -20° C. and titurated with ether (400 ml) to givea white solid which was isolated by filtration (4.1 g, 52%) m.p. 145-6°C. ¹ H NMR δ (CDCl₃) 2.85 (1H, m, H_(3a)), 3.31 (1H, m, H_(3b)), 3.88(3H, s, O--CH₃), 3.89 (3H, s, O--CH₃), 4.92 (1H, dd, J=4.92, 2.30 Hz,H₄), 6.30 (1H, br. singlet, N--H), 6.85 (1H, d, J=8.30 Hz, Ph--H), 7.00(1H, d, J=2.04 Hz, Ph--H), 7.09 (1H, dd, J=8.25, 2.06 Hz, Ph--H).

b. Methyl-(4-(3,4-dimethoxyphenyl)thio-2-oxoazetidin-1-yl)acetate

Sodium hydride (0.5 g, 12 mmol) in dry DMF (10 ml) was cooled to -5° C.and a solution of 4-(3,4-dimethoxyphenylthio)azetidin-2-one (3 g, 12mmol) in dry DMF (20 ml) was added dropwise over 15 mins under anitrogen atmosphere at -5° C. After 15 mins methylbromoacetate (2 g, 12mmol) was added in one portion, and the mixture stirred for 30 mins atroom temperature. The reaction mixture was carefully poured intobrine/ice water and ethyl acetate (100 ml) was added. The organic layerwas washed with brine (x2), dried (MgSO₄) and evaporated to a yellow oilwhich was purified by flash column chromatography eluted with petroleumether/ethyl acetate to give the product as a yellow oil (0.96 g, 25%yield).

c. (4-(3,4-Dimethoxyphenylthio)-2-oxoazetidin-1-yl)acetic acid

Prepared according to the general procedure of Example 201b and obtainedas a yellow oil.

d.N-(6phenylhexyl)-(4-(3,4-dimethoxyphenylthio)-2-oxoazetidin-1-yl)acetamide

Prepared according to the general procedure of Example 201c and obtainedas a colourless oil. ¹ H NMR δ (CDCl₃) 1.3-1.7 (8H, m, 4xCH₂), 2.59 (2H,t, J=7.6 Hz, CH₂ Ph), 2.89 (1H, dd, J=2, 15 Hz, H₃), 3.23 (2H, m,NHCH₂), 3.37 (1H, dd, J=5, 15 Hz, H₃), 3.73, 3.96 (each 1H, d, J=17 Hz,NCH₂), 3.87 (6H, s, 2xOCH₃), 4.99 (1H, m, H₄), 6.16 (1H, br s, NH),6.8-7.3 (8H, m, Ph--H+(CH₃ O)₂ Ph--H)

EXAMPLE 206(4R,SS/4S,SR)-N-(6-phenylhexyl)-(4-3,4-dimethoxyphenylsulfinyl)-2-oxoazetidin-1-yl)acetamide

Prepared according to the general procedure of Examples 202 & 3 andobtained as a yellow gum, 33% yield. ¹ H nmr δ (CDCl₃) 1.35-1.62 (8H, m,CH₂ CH₂ CH₂ CH₂), 2.58 (2H, t, J=7.0 Hz, CH₂ Ph), 3.15-3.45 (4H, m,H_(3a), H_(3b), NH--CH₂), 3.43, 3.82 (2H, dd, J=17.0, 17.0 Hz, N--CH₂),3.90-3.92 (6H, s, 2xOCH₃), 4.67 (1H, m, H₄), 6.75 (1H, s, NH), 6.96-7.29(8H, m, Ar--H, SO--Ph-(OMe)₂).

EXAMPLE 207 (4R,SR/4S,SS)N-(6-phenylhexyl)-(4-(3,4-dimethoxyphenylsulfinyl)-2-oxoazetidin-1-yl)acetamide

Prepared according to the general procedure of Examples 202 & 3 andobtained as a white solid m.p. 126-128° C., 26% yield. ¹ H nmr δ (CDCl₃)1.35-1.59 (8H, m, CH₂ CH₂ CH₂ CH₂), 2.59 (2H, t, J=7.0 Hz, CH₂ Ph), 2.78(1H, dd, J=15.0, 5.0 Hz, H_(3b)), 3.28 (2H, m, NH--CH₂). 3.47 (1H, dd,J=15.0, 2.0 Hz, H_(3a)), 3.87, 4.20 (2H, dd, J=17.0, 17.0 Hz, N--CH₂),3.93 (6H, s, 2xOCH₃), 4.51 (1H, m, H₄), 6.73 (1H, s, NH), 6.98-7.28 (8H,m, Ar--H, SO--Ph-(OMe)₂).

EXAMPLE 208N-(6-phenylhexyl)-(4-(4-chlorophenylthio)-2-oxoazetidin-1-yl)acetamide

Prepared from 4-(4-chlorophenyl)azetidin-2-one (H. Gu et. al., J. Org.Chem., 1990, 55, 5655) according to the general procedure of Example201. White crystalline solid, m.p. 52-4° C., 80% yield ¹ H NMR δ(CDCl₃), 1.33 (4H, m, NCH₂ CH₂ (CH₂)₂), 1.48 (2H, m, CH₂ CH₂ PhCl), 1.63(2H, m, NCH₂ CH₂), 2.60 (2H, t, J=7.4 Hz, CH₂ PhCl), 2.88 (1H, dd J=2.3,15.3 Hz, H_(3a)), 3.21 (2H, m, NHCH₂), 3.43 (1H, dd, J=5.0, 15.3 Hz,H_(3b)), 3.73, 4.00 (each 1H, d, J=16.6 Hz, NCH₂), 5.12 (1H, dd, J=2.3,5.0 Hz, H₄), 7.15-7.39 (Ph--H+ClPh--H).

EXAMPLE 209 4-(Phenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

To a cooled (cold water bath) solution of 4-phenylthioazetidin-2-one(Iwata-Reuyl et. al., J. Nat. Prod., 1993, 56(8), 1373) (1.9 g, 11mmol), tetra-n-butylammonium bromide (0.4 g, 1.1 mmol) and1-bromo-4-phenylbutan-2-one (Tetrahedron, 1970, 26, 5611) (2.7 g, 11.8mmol) in dry tetrahydrofuran (75 ml) was added freshly powderedpotassium hydroxide (1.8 g, 31 mmol), and the mixture stirred vigorouslyfor 2 hr at ambient temperature. Water was added and the productextracted into ethyl acetate, dried (MgSO₄) and evaporated to an oil.Treatment with ether/pet. ether (b.p. 40-60) gave the product as a whitecrystalline solid (1.8 g, 51%), mp 62-4° C. 1H NMR δ (CDCl₃), 2.63 (4H,m, CH₂ CO+CH₂ Ph), 2.85 (3H, m, CH₂ Ph+H_(3a)), 3.44 (1H, dd, J=5.0,15.1 Hz, H_(3b)) 3.73, 4.27 (each 1H, d, J=18.5 Hz, NCH₂), 5.21 (1H, dd,J=2.3, 4.9 Hz, H₄), 6.97-7.40 (10H, m, Ph--H). Found: C, 70.0; H, 5.9;N, 4.4%; C₁₉ H₁₉ NO₂ S requires: C, 70.1; H, 5.9; N, 4.3%

The following compounds (examples 210 to 215) were prepared according tothe general procedure of Example 209. The (R)- and(S)-4-phenylthioazetidinones for Examples 210 and 211 were prepared bythe method describe din A. Basak, Synth. Commun. 23, 1985, 1993

EXAMPLE 210 (S)-4-(Phenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Colourless oil, 54% yield ¹ H NMR δ (CDCl₃), 2.63 (4H, m, CH₂ CO+CH₂Ph), 2.85 (3H, m, CH₂ Ph+H_(3a)), 3.44 (1H, dd, J=5.0, 15.1 Hz, H_(3b))3.73, 4.27 (each 1H, d, J=18.5 Hz, NCH₂), 5.21 (1H, dd, J=2.3, 4.9 Hz,H₄), 6.97-7.40 (10H, m, Ph--H). Found: C, 69.9; H, 6.0; N, 4.4%; C₁₉ H₁₉NO₂ S requires: C, 70.1; H, 5.9; N, 4.3% [a]_(D) =+92.7° (c 0.49,chloroform, 25° C.)

EXAMPLE 211 (R)-4-(Phenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Colourless oil, 63% yield ¹ H NMR δ (CDCl₃), 2.63 (4H, m, CH₂ CO+CH₂Ph), 2.85 (3H, m, CH₂ Ph+H_(3a)), 3.44 (1H, dd, J=5.0, 15.1 Hz, H_(3b))3.73, 4.27 (each 1H, d, J=18.5 Hz, NCH₂), 5.21 (1H, dd, J=2.3, 4.9 Hz,H₄), 6.97-7.40 (10H, m, Ph--H). Found: C, 69.3; H, 5.9; N, 4.4%; C₁₉ H₁₉NO₂ S. 0.2 H₂ O requires: C, 69.4; H, 5.9; N, 4.3%; [a]_(D) =-88.7° (c0.47, chloroform, 25° C.)

EXAMPLE 2124-(2-Methoxyphenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

a. 4-(2-Methoxyphenylthio)azetidin-2-one

Prepared from 2-methoxythiophenol using the general procedure of example205a and obtained as a white crystalline solid, m.p. 103-5° C., 81%yield ¹ H NMR δ (CDCl₃), 2.95 (1H, m, H_(3a)), 3.39, (1H, m, H_(3b)),3.90 (1H, s, CH₃ OPh), 4.98 (1H, dd, J=2.4, 5.0 Hz, H₄), 6.33 (1H, s,NH), 6.96 (2H, m, 3,5-(2-CH₃ OPh)-H), 7.39 (2H, m, 4,6-(2-CH₃ OPh)-H).

b. 4-(2-Methoxyphenythio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Colourless oil, 76% yield ¹ H NMR δ (CDCl₃), 2.59 (2H, m, CH₂ CO), 2.81(2H, m, CH₂ Ph), 2.93 (1H, dd, J=1.7, 14.9 Hz, H_(3a)), 3.36 (1H, dd,J=5.0, 151 Hz, H_(3b)), 3.77, 4.22 (each 1H, d, J=18.6 Hz, NCH₂), 3.86(3H, s, OCH₃), 5.27 (1H, dd, J=2.3, 4.9 Hz, H₄), 6.90 (2H, m, 3,5-(2-CH₃OPh)-H), 7.12-7.39 (7H, m, 4,6-(2-CH₃ OPh)-H+Ph--H). Found: C, 67.6; H,6.0; N, 3.9%; C₂₀ H₂₁ NO₃ S requires: C, 67.6; H, 6.0; N, 3.9%

EXAMPLE 2134-(3,4-dimethoxyphenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Colourless oil, 77% yield ¹ H NMR δ (CDCl₃), 2.63-2.70 (2H, m, CH₂ Ph),2.77-2.90 (3H, m, COCH₂, H_(3a)), 3.38 (1H, dd, J=15.03, 4.96 Hz,H_(3b)), 3.77 and 4.26 (1H each, d, J=18.41 Hz, N--CH₂), 3.86 and 3.87(3H each, s, OCH₃), 5.11 (1H, dd, J=4.94, 2.29, H₄), 6.79 (1H, d,J=8.26, Ph--H), 6.90-6.98 (2H, m, Ph--H), 7.12-7.32 (5H, m, Ph--H).

EXAMPLE 2144-(3,-methoxyphenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

a. 4-(3-methoxyphenylthio)azetidin-2-one

Prepared from 3-methoxythiophenol using the general procedure of example205a and obtained as a white crystalline solid, mp 55-6° C., 86% yield1H NMR δ (CDCl₃) 2.90 (1H, m, H_(3a)), 3.38 (1H, m, H_(3b)), 3.80 (3H,s, OCH₃), 5.02 (1H, dd, J=4.94, 2.33 Hz, H₄), 6.64 (1H, br. singlet,N--H), 6.85-6.90 (1H, m, Ph--H), 6.96-7.03 (2H, m, Ph--H), 7.23-7.30(1H, m, Ph--H).

b. 4-(3-methoxyphenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Yellow oil, 86% yield 1H NMR δ (CDCl₃) 2.50-2.97 (5H, m, CH₂ CH₂,H_(3a)), 3.45 (1H, dd, J=15.0, 4.97 Hz, H_(3b)), 3.73, 4.27 (1H each, d,J=18.55 Hz, N--CH₂), 3.78 (3H, s, OCH₃), 5.24 (1H, dd, J=4.97, 2.34 Hz,H₄), 6.84 (1H, m, Ph--H), 6.91-6.96 (2H, m, Ph--H), 7.12-7.31 (6H, m,Ph--H).

EXAMPLE 2154-(4-methoxyphenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, mp 57-58° C., 80% yield Found: C, 67.4; H, 6.0;N, 4.1%; C₂₀ H₂₁ NO₃ S requires: C, 67.8; H, 6.0; N, 3.9%

EXAMPLE 216 (4R,SR/4S,SS)4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

A solution of 4-phenylthio-N-(4-phenyl-2-oxobutyl)azetidin-2-one (2.3 g,7 mmol) in dichloromethane (80 ml) was cooled to -50 to -60° C. and asolution of m-chloroperbenzoic acid (1.5 g, 9 mmol) in dichloromethane(60 ml) was added dropwise with stirring over 40 min. After a further 2hr. at -50 to -60° C. another portion of m-chloroperbenzoic acid (61 mg,0.35 mmol) was added and stirring continued for 30 min. The reactionmixture was then shaken with a mixture of saturated aqueous sodiumsulphite and saturated sodium hydrogen carbonate and the organic layercollected, dried (MgSO₄) and evaporated. Crystallisation from ether thendichloromethane/ether gave the product as a white crystalline solid, mp125-6° C., 27% yield 1H NMR δ (CDCl₃), 2.78 (2H, m, CH₂ CO), 2.87 (1H,dd, J=4.7, 15.0 Hz, H_(3a)), 2.94 (2H, m, CH₂ Ph), 3.42 (1H, dd, J=2.0,15.0 Hz, H_(3b)), 3.85, 4.46 (each 1H, d, J=18.9 Hz, CH₂ N), 4.73 (1H,dd, J=2.1, 4.7 Hz, H₄), 7.17-7.35 (5H, m, Ph--H), 7.55 (5H, s, SOPh--H).Found: C, 66.7; H, 5.7; N, 4.2%; C₁₉ H₁₉ NO₃ S requires: C, 66.8; H,5.6; N, 4.1%

EXAMPLE 217(4R,SS/4S,SR)-4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

The combined filtrate from Example 216 was evaporated and the residuepurified by flash chromatography (silica, ethyl acetate/pet. ether). theproduct crystallised from ether to give the product as a whitecrystalline solid, mp 111-3° C., 16% yield 1H NMR δ (CDCl₃), 2.38-2.62(2H, m, CH₂ CO), 2.81 (2H, m, CH₂ Ph), 3.13-3.30 (2H, m, H_(3a)+H_(3b)), 3.73, 4.30 (each 1H, d, J=18.8 Hz, CH₂ N), 4.80 (1H, dd,J=2.8, 4.8 Hz, H₄), 7.11-7.33 (5H, m, Ph--H), 7.50-7.65 ((5H, m,SOPh--H). Found: C, 66.4; H, 5.6; N, 4.3%; C₁₉ H₁₉ NO₃ S requires: C,66.8; H, 5.6; N, 4.1%

The following compounds (Examples 218-26) were prepared following thegeneral procedure of Examples 216 and 17.

EXAMPLE 218(4R,SR)-4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, m.p. 123-4° C., 26% yield from Example 211. 1HNMR δ (CDCl₃), 2.78 (2H, m, CH₂ CO), 2.87 (1H, dd, J=4.7, 15.0 Hz,H_(3a)), 2.94 (2H, m, CH₂ Ph), 3.42 (1H, dd, J=2.0, 150 Hz, H_(3b)),3.85, 4.46 (each 1H, d, J=18.9 Hz, CH₂ N), 4.73 (1H, dd, J=2.1, 4.7 Hz,H₄), 7.17-7.35 (5H, m, Ph--H), 7.55 (5H, s, SOPh--H Found: C, 66.3; H,5.6; N, 4.4%; C₁₉ H₁₉ NO₃ S. 0.15 H₂ O requires: C, 66.3; H, 5.7; N,4.1% [a]_(D) =-309.69° (c 0.42, chloroform, 25° C.)

EXAMPLE 219(4R,SS)-4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, m.p. 49-51° C., 6% yield from Example 211. 1HNMR δ (CDCl₃), 2.38-2.62 (2H, m, CH₂ CO), 2.81 (2H, m, CH₂ Ph),3.13-3.30 (2H, m, H_(3a) +H_(3b)), 3.73, 4.30 (each 1H, d, J=18.8 Hz,CH₂ N), 4.80 (1H, dd, J=2.8, 4.8 Hz, H₄), 7.11-7.33 (5H, m, Ph--H),7.50-7.65 (5H, m, SOPh--H). Found: C, 66.3; H, 5.7; N, 4.5%; C₁₉ H₁₉ NO₃S. 0.15 CH₃ CN requires: C, 66.7; H, 5.6; N, 4.6% [a]_(D) =+161.8° (c0.1, chloroform, 25° C.)

EXAMPLE 220 (4R,SR/4S,SS)4-(2-Methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, m.p. 129-31° C., 12% yield 1H NMR δ (CDCl₃),2.79 (3H, m, H_(3a) +CH2CO), 2.96 (2H, m, CH₂ Ph), 3.35 (1H, dd, J=1.6,14.9 Hz, H_(3b)), 3.87 (3H, s, OCH₃), 3.93, 4.50 (each 1H, d, J=18.9 Hz,NCH₂), 5.13 (1H, dd, J=2.1, 4.7 Hz, H₄), 6.93 (1H, d, 3-(2-CH₃ OPh)-H),7.16-7.34 (6H, Ph--H+5-(2-CH₃ OPh)-H), 7.49 (1H, m, 4-(2-CH₃ OPh)-H),7.67 (1H, dd, 6-(2-CH₃ OPh)-H). Found: C, 64.0; H, 5.8; N, 3.9%; C₂₀ H₂₁NO₄ S. 0.2 H₂ O requires: C, 64.0; H, 5.8; N, 3.7%

EXAMPLE 221(4R,SS/4S,SR)-4-(2-Methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, m.p. 85-7° C., 31% yield 1H NMR δ (CDCl₃),2.20, 2.44 (2H, m, CH2CO), 2.67 (2H, m, CH₂ Ph), 3.26-3.45 (2H, m,H_(3a) +H_(3b)), 3.39, 4.22 (each 1H, d, J=19.1 Hz, NCH₂), 3.85 (3H, s,OCH₃), 5.36 (1H, dd, J=2.5, 4.9 Hz, H₄), 6.83 (1H, d, 3-(2-CH₃ OPh)-H),7.08-7.32 (6H, m, 5-(2-CH₃ OPh)-H+Ph--H), 7.46 (1H, m, 4-(2-CH₃ OPh)-H),7.76 (1H, dd, 6-(2-CH₃ OPh)-H). Found: C, 64.2; H, 5.7; N, 3.7%; C₂₀ H₂₁NO₄ S requires: C, 64.7; H, 5.7; N, 3.8%

EXAMPLE 222(4R,SS/4S,SR)-4-(3,4-dimethoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, m.p. 110-112° C., 11% yield Found: C, 62.6; H,5.8; N, 3.7%; C₂₁ H₂₃ NO₅ S requires: C, 62.8; H, 5.8; N, 3.5%

EXAMPLE 223(4R,SR/4S,SS)-4-(3-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, m.p. 94-95° C., 15% yield Found: C, 64.4; H,5.7; N, 3.9%; C₂₀ H₂₁ NO₄ S requires: C, 64.7; H, 5.7; N, 3.8%

EXAMPLE 224(4R,SS/4S,SR)-4-(3-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, m.p. 88-90° C., 4% yield Found: C, 64.4; H,5.7; N, 3.9%; C₂₀ H₂₁ NO₄ S requires: C, 64.7; H, 5.7; N, 3.8%

EXAMPLE 225(4R,SR/4S,SS)-4-(4-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, m.p. 154-155° C., 42% yield Found: C, 64.6; H,5.8; N, 3.9%; C₂₀ H₂₁ NO₄ S requires: C, 64.7; H, 5.7; N, 3.8%

EXAMPLE 226(4R,SS/4S,SR)-4-(4-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

White crystalline solid, m.p. 67-69° C., 13.5% yield Found: C, 64.6; H,5.8; N, 3.9%; C₂₀ H₂₁ NO₄ S requires: C, 64.7; H, 5.7; N, 3.8%

EXAMPLE 224 4-Phenylsulphonyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

To a cooled and stirring solution of4-(phenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one (0.5 g, 1.54 mmol)in dichloromethane (20 ml) was added dropwise a solution ofm-chloroperbenzoic acid (0.66 g, 3.84 mmol) in dichloromethane (25 ml).The cooling bath was removed and a further portion of m-chloroperbenzoicacid (0.13 g, 0.75 mmol) added to complete the reaction. After 30 min.,the mixture was shaken with a mixture of saturated aqueous sodiumsulphite and saturated sodium hydrogen carbonate and the organic layercollected, dried (MgSO₄) and evaporated to an oil which crystallisedunder pet. ether. Recrystallisation from dichloromethane-ether gave thetitle compound as a white solid, yield 0.45 g (82%), m.p. 110-11° C. 1HNMR δ (CDCl₃), 2.68 (2H, m, CH₂ CO), 2.89 (2H, t, CH₂ Ph), 3.06 (1H, dd,J=1.9, 15.3 Hz, H_(3a)), 3.35 (1H, dd, J=5.2, 15.1 Hz, H_(3b)), 3.94,4.41 (each 1H, d, J=18.8 Hz, CH₂ N), 5.02 (1H, dd, J=2.2, 5.2 Hz, H₄),7.15-7.34 (5H, m, Ph--H), 7.58-7.89 (5H, m, SO₂ Ph--H). Found: C, 63.4;H, 5.4; N, 4.2%; C₁₉ H₁₉ NO₄ S requires: C, 63.9; H, 5.4; N, 3.9%

EXAMPLE 2284-(2-Methoxyphenylsulphonyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one

Prepared according to the general procedure of Example 227 and obtainedas a white crystalline solid, m.p. 122-3° C., 70% yield 1H NMR δ(CDCl₃), 2.44 (2H, m, CH2CO), 2.57 (2H, m, CH₂ Ph), 3.37 (2H, m, H_(3a)+H_(3b)), 3.67, 4.36 (each 1H, d, J=19.0 Hz, NCH₂), 3.93 (3H, s, OCH₃),5.49 (1H, dd, J=2.7, 4.7 Hz, H₄), 6.99 (1H, d, 3-(2-CH₃ OPh)-H),7.11-7.33 (6H, m, 5-(2-CH₃ OPh)-H+Ph--H), 7.63 (1H, m, 4-(2-CH₃ OPh)-H),7.93 (1H, dd, 6-(2-CH₃ OPh)-H). Found: C, 61.8; H, 5.5; N, 3.7%; C₂₀ H₂₁NO₅ S requires: C, 62.0; H, 5.5; N, 3.6%

EXAMPLE 229N-[6-(4-Chlorophenyl)hexyl]-4-(4-methylphenylthio)-2-oxoazetidin-1-ylacetamide

a. 6-(3-chlorophenyl)hexyn-1-ol

A mixture of 3-chloroiodobenzene (14.3 g, 60 mmol),tetrakis(triphenylphosphine) palladium (2.1 g, 1.8 mmol) and5-hexyn-1-ol (5.9 g, 60 mmol) in triethylamine (120 ml) was stirred at25° C. for 3H and partitioned between water and ether. The

White crystalline solid, m.p. 88-90° C., 4% yield ether layer wasseparated and the aqueous extracted with ether. The combined etherextracts were washed with 1N HCl and dried (Na₂ SO₄). The ether wasevaporated and the residue purified by flash chromatography on silicausing dichloromethane as eluant. Evaporation of the appropriatefractions gave the product alcohol as an oil (11.5 g, 92%).

b. 1-(Phthalimido)-6-(3-chlorophenyl)hex-1yne

A solution of 6-(3-chlorophenyl)hexyn-1-ol (11.5 g, 55 mmol),triphenylphosphine (14.5 g, 55 mol) and phthalimide (8.1 g, 55 mol) indry THF (110 ml) was treated with a solution of diethylazodicarboxylate(9.6 g, 55 mmol) in THF (20 mol) over several minutes. After 16 h,violates were removed in vacuo and the residue treated with ether. Theprecipitated solid was removed, the filtrate evaporated and the residuepurified by flash chromatography on silica using dichloromethane aseluant. Evaporation of the appropriate fractions gave the product as asolid (16.5 g, 89%)

c. 6-(3-Chlorophenyl)hexylamine

A suspension of 1-(phthalimido)-6-(3-chlorophenyl)hex-1-yne (10 g, 30mmol) in methanol (100 ml) was treated with platinum oxide (250 mg) andthe mixture hydrogenated at 50 psi for 72 h. Further quantities ofcatalyst were added at intervals and when the theoretical uptake ofhydrogen was complete, the mixture was filtered and the filtrateevaporated to a brown oil (9.5 g, 96%). This was dissolved in ethanol(100 ml) and treated with hydrazine hydrate (2.8 g, 56 mmol) underreflux for 16 h. The mixture was cooled to 5°

c. and the precipitated solid removed by filtration. Evaporation of thefiltrate gave an oil which was taken up in ether, washed with water,dried (Na₂ SO₄) and evaporated to a brown oil (5.8 g, 98%)

d. N-[6-(4-Chlorophenyl)hexyl]-1-bromoacetamide

A cooled solution of 6-(4-chlorophenyl)hexylamine (20 g) and Hunig'sbase (12.15 g) in dry dichloromethane (250 ml) was treated withbromoacetylbromide (190 g) in dichloromethane (50 ml) at 0-5° C. Afterworkup and chromatography N-[6-(4-chlorophenyl)hexyl]-1-bromoacetamidewas obtained as a white solid, (20.4 g, 65% yield), m.p. 63-65° C.

e. 4-Methylphenylthio-2-oxo-azetidin-1-one

4-Methylphenylthio-2-oxo-azetidin-1-one was prepared from4-methylphenylthiol and 4-acetoxyazetidinone in the presence of sodiumethoxide in ethanol and was isolated as a cream solid, m.p. 105-107° C.,4.3% yield; ¹ H NMR δ (CDCl₃) 2.35(3H s, CH₃), 2.85,3.32(each 1H, dd,J=2.5,15 Hz, H_(3a)), 3.34,3.40 (1H, dd, J=5.15 Hz, H_(3b)), 4.93 (1H,m, H₄), 5.03 (1H, m, H₄), 6.41 (1H, bs, NH), 7.14 (2H, d, J=10 Hz,Ph-H), 7.36 (2H, d, J=10 Hz, Ph-H).

f.N-[6-(4-Chlorophenyl)hexyl]-4-(4-methylphenylthio)-2-oxoazetidin-1-ylacetamide

4-(4-Methylphenylthio)-2-oxoazetidinone (2.5 g) was treatedN-[6-(4-chlorophenyl)hexyl]-1-bromoacetamide (4.3 g) in dry THF (100 ml)in the presence of 18-crown-6 (˜5 mg) and tetra-n-butylammonium bromide(1.44 g) to giveN-[6-(4-chlorophenyl)hexyl]-4-(4-methylphenylthio)-2-oxoazetidin-1-ylacetamide(2.35 g, 43% yield) as colourless microprisms, m.p. 63-65° C., afterchromatography. ¹ NMR δ (CDCl₃)1.28-1.34(2H, m, CH₂),1.45-1.60(4H, m,(CH₂)₂), 2.6 (2H, t, J=7.75 Hz, CH₂), 2.89,290(each 1H, dd, J=2.5,15 Hz,H_(3a)), 2.85 (2H, q, J=7.5 Hz, NHCH₂) 3.34,3.40 (1H, dd, J=5,15 Hz,H_(3b)), 3.80,3.96 (each 1H, dd, J=19.00 Hz, NCH₂), 5.03 (1H, m, H₄),6.14 (1H, bs, NH), 7.06-7.32 (8H, m, Ph-H).

EXAMPLE 230(R,R/S,S)-N-[6-(4-chlorophenyl)hexyl]-4-(4-methylphenyl)sulfinyl-2-oxo-azetidinyl-1-ylacetamide

Treatment ofN-[6-(4-chlorophenyl)hexyl]-4-(4-methylphenylthio)-2-oxoazetidin-1-ylacetamidewith mCPBA as for Example 202 gave the title compound as whitemicroprisms after crystallisation from the mixture of diastereoisomers,m.p. 133-134° C., 32% yield; ν _(c)═o 1790,1690 cm⁻¹

Found: C, 62.3; H, 6.2; N, 6.0%; C₂₄ H₂₉ ClN₂ O₃ S requires:C, 62.5; H,6.3; N, 6.1%

EXAMPLE 231(R,S/S,R)-N-[6-(4-chlorophenyl)hexyl]-4-(4-methylphenyl)sulfinyl-2-oxo-azetidinyl-1-ylacetamide

Evaporation of the mother liquors from the crystallisation in Example230 yielded the title compound as a waxy solid, m.p. indeterminate, 11%yield; ν _(c)═o 1791,1690 cm⁻¹. Found: C, 60.2; H, 6.0; N, 5.8%; C₂₄ H₂₉ClN₂ O₃ S.1H₂ O requires: C, 60.5; H, 6.5; N, 5.9%

EXAMPLE 232N-[6-(4-chlorophenyl)hexyl]-4-(4-methylphenyl)sulfonyl-2-oxo-azetidinyl-1-ylacetamide

Treatment ofN-[6-(4-chlorophenyl)hexyl]-4-(4-methylphenylthio)-2-oxoazetidin-1-ylacetamidewith mCPBA (2 equivalents) as for Example 204 gave the title compound aswhite microprisms, m.p. 132-133° C., 71% yield; ν _(c)═o 1794, 1690 cm⁻¹Found:C, 60.1; H, 6.1; N, 5.9%; C₂₄ H₂₉ ClN₂ O₄ S requires: C, 60.4; H,6.1; N, 5.9%

EXAMPLE 233(+/-)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylthio-2-oxoazitedin-1-ylacetamidehydrate

Treatment (4-phenylthio-2-oxo)azitedin-1-ylacetic acid with6-(4-chlorophenyl)hexylamine under the conditions described in Example201 gave the title compound as colourless crystals, m.p. 57-9° C., 96%yield; Found: C,61.3; H, 6.3; N, 6.3%; C₂₃ H₂₇ ClN₂ O₂ S.H₂ O requires:C, 61.5; H, 6.3; N, 6.5%

The above racemic compound (Example 233) was separated by highperformance liquid chromatography on a chiral support to give theconstitutive enantiomers (Examples 234, 35)

EXAMPLE 234(-)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylthio-2-oxoazitedin-1-ylacetamidehydrate

Colourless oil, [α]_(D) ²⁰ =-59.9 (CHCl₃, c=0.2%w/v)

EXAMPLE 235(+)-N-[6(4-Chlorophenyl)hexyl]-4-phenylthio-2-oxoazitedin-1-ylacetamidehydrate

Colourless oil, [α]_(D) ²⁰ =+56.0 (CHCl₃, c=0.3%)

Treatment of(+/-)-N-[6-(4-chlorophenyl)hexyl]-4-phenylthio-2-oxoazitedin-1-ylacetamidewith mCPBA as described for Examples 202 and 203 gave the followingsulfoxides (Examples 236, 237).

EXAMPLE 236(R,R/S,S)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colourless solid, m.p. 110-111° C., 23% yield

Found: C, 61.7; H, 6.1; N, 6.3%; C₂₃ H₂₇ ClN₂ O₃ S requires:C, 61.8; H,6.1; N, 6.3%

EXAMPLE 237(R,S/S,R)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colourless crystals, m.p. 85-88° C., 30% yield

Found: C, 61.9; H, 6.1; N, 6.3%; C₂₃ H₂₇ ClN₂ O₃ S requires: C, 61.8; H,6.1; N, 6.3%

(R,R/S,S)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide(Example 236) was separated by high performance liquid chromatography ona chiral support to give the constitutive enantiomers (Examples 238,39).

EXAMPLE 238 (-)-(R,R orS,S)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colourless solid, m.p. 115-118° C., [α]_(D) ²⁰ =-238.6 (CHCl₃, c=0.04%w/v)

EXAMPLE 239 (+)-(R,S orS,R)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colourless solid, m.p. 116-118.5° C., [α]_(D) ²⁰ =+251.5 (CHCl₃, c=0.03%w/v)

(R,S/S,R)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide(Example 237) was separated by high performance liquid chromatography ona chiral support to give the constitutive enantiomers (Examples 240,41).

EXAMPLE 240 (+)-(R,S orS,R)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colourless solid, m.p. 115-116.5° C., [α]_(D) ²⁰ =+188.6 (CHCl₃, c=0.04%w/v)

EXAMPLE 241 (-)-(R,R, orS,S)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colourless solid, m.p. 113-115° C., [α]_(D) ²⁰ =-212.8 (CHCl₃, c=0.04%w/v)

EXAMPLE 242N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide

Treatment of(R,R/S,S)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamidewith mCPBA in dichloromethane gave the title compound as colourlesscrystals, m.p. 144-146° C., 92%

Found: C, 59.6; H, 5.9; N, 6.1%; C₂₃ H₂₇ ClN₂ O₄ S requires: C, 59.7; H,5.9; N, 6.1%

(+/-)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide(Example 242) was separated by high performance liquid chromatography ona chiral support to give the constitutive enantiomers (Examples 243,244).

EXAMPLE 243(-)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide

Colourless solid, m.p. 106-109° C., [α]_(D) ²⁰ =-67.7 (CHCl₃, c=0.07%w/v)

EXAMPLE 244(+)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide

Colourless solid, m.p. 110-111° C., [α]_(D) ²⁰ =+69.1 (CHCl₃, c=0.08%w/v)

EXAMPLE 245N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxyphenylthio)-2-oxoazetidin-1-ylacetamide

The title compound was prepared by the methods described in Example 201and was isolated as colourless crystals, m.p. 84-86° C., in 94% yield.

Found: C, 62.4; H, 6.3; N, 6.1%; C₂₄ H₂₉ ClN₂ O₃ S requires:C, 62.5; H,6.3; N, 6.1%

Treatment ofN-[6-(4-chlorophenyl)hexyl]-4-(4-methoxyphenylthio)-2-oxoazetidin-1-ylacetamidewith mCPBA as described for Examples 202 and 203 gave the followingsulfoxide diastereoisomers (Examples 246, 247).

EXAMPLE 246(R,R/S,S)-N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxyphenylsulfinyl)-2-oxoazetidin-1-ylacetamide

Colourless crystals, m.p. 114-116° C., 39% yield.

Found: C, 60.1; H, 6.0; N, 6.0%; C₂₄ H₂₉ ClN₂ O₄ S requires: C, 60.4; H,6.1; N, 5.9%

EXAMPLE 247(R,S/S,R)-N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxyphenylsulfinyl)-2-oxoazetidin-1-ylacetamide

Colourless crystals, m.p. 74-77° C., 24% yield

Found: C, 60.5; H, 6.0; N, 5.9%; C₂₄ H₂₉ ClN₂ O₄ S requires: C, 60.4; H,6.1; N, 5.9%

EXAMPLE 248N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxyphenylsulfonyl)-2-oxoazetidin-1-ylacetamide

Treatment of(R,R/S,S)-N-[6-(4-chlorophenyl)hexyl]-4-(4-methoxyphenylsulfinyl)-2-oxoazetidin-1-ylacetamidewith mCPBA gave the title compound as colourless crystals, m.p. 105-7°C., 91% yield;

Found: C, 58.6; H, 5.9; N, 5.8%; C₂₄ H₂₉ ClN₂ O₅ S requires: C, 58.5; H,5.9; N, 5.7%

EXAMPLE 249N-Benzyl-[4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl]acetamide

Treatment of (4-(4-methoxyphenylthio)-2-oxoazetidin-1yl)acetic acid withbenzylamine under the conditions described in Example 86 gave the titlecompound as a colourless oil, 74% yield. ¹ H NMR δ (CDCl₃) 2.80, 2.86(1H, dd, J=2.3, 15.2 Hz, H₃), 3.29, 3.35 (1H, dd, J=5, 15.2 Hz, H₃),3.79 (3H, s, OCH₃), 3.85, 4.05 (each 1H, d, J=16.7 Hz, NCH₂), 4.43 (2H,d, J=5.7 Hz, NHCH₂), 4.97 (1H, m, H₄) 6.5 (1H, m, NH), 6.83 (2H, d,J=8.6 Hz, 4-OCH₃ Ph-H), 7.24-7.35 (7H, m, Ph-H, 4-OCH₃ Ph-H). ν _(c)═o1775 cm⁻¹. Found: C, 64.0 H, 5.8; N, 8.1%. C₁₉ H₂₀ N₂ O₃ S requires: C,64.0; H, 5.7 N, 7.9%

Treatment ofN-benzyl-[4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl]acetamide withmCPBA followed by recryatallisation as described for Examples 2 and 3gave the compounds described in Examples 250 and 251.

EXAMPLE 250N-Benzyl-[4-(4-methoxyphenylsulphinyl)-2-oxoazetidin-1-yl]acetamide(Diastereomer 1)

Colourless solid, m.p. 165° C., 35% yield. ¹ H NMR δ (CDCl₃) 2.75, 2.81(1H, dd, J=4.7, 15 Hz, H₃), 3.41, 3.47 (1H, dd, J=2.2, 15 Hz, H₃), 3.86(3H, s, OCH₃), 3.99, 4.16 (each 1H, d, J=17.2 Hz, NCH₂), 4.47 (2H, m,NHCH₂), 4.55 (1H, m, H₄), 7.05 (2H, m, 4-OCH₃ Ph-H), 7.1 (1H, m, NH),7.33 (5H, m, Ph-H), 7.47 (2H, m, 4-OCH₃ Ph-H). ν _(c)═o 1791 cm⁻¹.Found: C, 61.3 H, 5.4; N, 7.5%. C₁₉ H₂₀ N₂ O₄ S requires: C, 61.3; H,5.4 N, 7.5%

EXAMPLE 251N-Benzyl-[4-(4-methoxyphenylsulphinyl)-2-oxoazetidin-1-yl]acetamide(Diastereomer 2)

Foam, 21% yield. ¹ H NMR δ (CDCl₃) 3.23 (2H, m, 2x, H₃), 3.35, 3.89(each 1H, d, J=16.9 Hz, NCH₂), 3.83 (3H, s, OCH₃), 4.39, 4.57 (2H, 2xdof d, J=6,15 Hz, NHCH₂), 4.65 (1H, m, H₄), 6.90 (2H, m, 4-OCH₃ Ph-H),7.26-7.50 (7H, m, Ph-H, 4-OCH₃ Ph-H), 7.60 (1H, m, NH). ν _(v)═o 1790cm⁻¹. Found: C, 60.9; H, 5.5; N, 7.4%. C₁₉ H₂₀ N₂ O₂ S requires: C,61.3; H, 5.4 N, 7.5%

EXAMPLE 301 Methyl (4-(4-methoxybenzylthio)-2-oxoazetidin-1-yl)acetate

Treatment of 4-(4-methoxybenzylthio)-azetidin-2-one (7 g) with methylbromoacetate (5.3 g) under the conditions described for Example 29a gavethe title compound as a colourless solid, m.p. 45-46° C., (5.9 g, 64%)

EXAMPLE 302 Methyl (4-methoxyphenylthio-2-oxoazetidin-1-yl)acetate

To a solution of 4-(4-methoxyphenylthio)azetidin-2-one (H. Gu et. al.,J. Org. Chem., 1990, 55, 5655) (11.6 g, 55 mmol), methyl bromoacetate(9.2 g, 60 mmol) and tetrabutylammonium bromide (1.8 g, 0.56 mmol) indry THF (300 ml) was added powdered potassium hydroxide (3.4 g, 60mmol). The resulting mixture was stirred for two hours at roomtemperature before water (100 ml) was added. The solution was extractedwith ethyl acetate (3×150 ml portions) and the combined extracts dried(MgSO₄) and evaporated. The residue was purified by flash chromatographyon silica gel eluted with ethyl acetate/hexane (1:1→2:1) to give theproduct as a solid m.p. 101-103° C., 58% yield

¹ H NMR δ (CDCl₃) 2.80(1H, dd, J=2.2,15 Hz H_(3a)), 3.34 (1H, dd, J=5,15Hz, H_(3b)), 3.72 (3H, s, OCH₃), 3.77,4.29 (each 1H, d, J=18.00 Hz,NCH₂), 3.80 (3H, s, SCH₃), 5.07 (1H, m, H₄), 6.87 (2H, d, J=10 Hz,2,6Ph-H), 7.35 (2H, d, J=10 Hz, 3,5Ph-H).

EXAMPLE 303 Methyl (4-phenylthio-2-oxoazetidin-1-yl)acetate

Treatment of 4-phenylthioazetidin-2-one (Iwata-Reuyl et. al., J. Nat.Prod., 1993, 56(8), 1373) (8 g) with methyl bromoacetate (7.5 g) underthe conditions described for Example 1b gave the title compound as acolourless oil (6 g, 53% yield). ¹ H NMR δ (CDCl₃) 2.87 (1H, dd,H_(3a)), 3.42 (1H, dd, H_(3b)), 3.70 (3H, s, CH₃), 3.75, 4.29 (each 1H,d, NCH₂), 5.22, (1H, dd, H₄), 7.26-7.46 (5H, m, Ph-H).

EXAMPLE 304 Methyl[(3S,4R)-4-benzylthio-3-chloro-2-oxoxazetidin-1-yl)acetate

a. Method (6S)-chloropenicillanate 1-oxide

A solution of methyl (6S)-chloropenicillanate (13.34 g, 0.0534 mol)(Tet.Lett. No.11, p1205-1210, 1966) in dichloromethane (200 ml) wascooled to -70° C. and treated with a solution of 3-chloroperoxybenzoicacid (16.76 g, 0.0534 mol) in dichloromethane (400 ml) over 1 hourmaintaining temperature at -70° C. The cooling bath was removed and thereaction was stirred for 1.5 hr. A solution of 3-chloroperoxybenzoicacid (0.5 g) in dichloromethane (100 ml) was added and stirred for 30minutes. The reaction mixture was washed successively with 10% aq.sodium sulphite, sat. NaHCO₃, water, dried (MgSO₄) and evaporated.Purification by flash chomatography (silica, pet.ether-ethyl acetate)gave the title compound as a colourless oil, 14.1 g (99%).

b. Methyl2-[(3S,4R)-4-acetylthio-3-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate

A mixture of methyl (6S)-chloropenicillanate 1-oxide (13.94 g, 0.0625mol), acetic anhydride (24.7 ml, 0.2618 mol) and triisopropyl phosphite(14.25 ml, 0.0578 mol) in benzene (150 ml) was stirred at reflux for 21hr. The solvents were evaporated and the residue revaporated twice fromxylene. The orange oil was diluted with ethyl acetate (150 ml) andtreated with triethylamine (0.53 g, 0.00524 mol) and stirred for 1 hr.The reaction was washed successively with 5% aq. citric acid, brine,5%aq. NaHCO₃, brine, dried (MgSO₄), and evaporated to a brown oil.Distillation to remove volatile impuities and chromatography (silica,dichloromethane), followed by precipitation from pet. ether gave thetitle compound as a cream solid, 6.7 g (44%, m.p. 62-63° C.).

c. Methyl [(3S,4R)-4-acetylthio-3-chloro-2-oxo-azetidin-1-yl]acetate

Ozonised oxygen was bubbled through a solution of methyl2-[(3S,4R)-4-acetylthio-3-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(7.6 g, 0.026 mol) in ethyl acetate (300 ml) at -65 to -70° C. until apermanent blue colour was obtained. Excess ozone was removed by thepassage of oxygen, then trimethyl phosphite (30.7 ml, 0.26 mol) wasadded dropwise. After 15 minutes the solution was allowed to warm toroom temperature and stirred for 19 hr. The solvents were evaporated andthe residue reevaporated twice from toluene, then disolved in ethylacetate (175 ml) and stirred vigourously with a solution ofp-toluenesulphonic acid (1.14 g) in water (60 ml). After dilution withwater the organic layer was separated and the aqueous layer furtherextracted with ethyl acetate. The combined organic extracts were washedsuccessively with saturated aq. sodium hydrogen carbonate and brine,dried (MgSO₄) and evaporated. Purification by flash chromatography(silica, pet. ether-ethyl acetate) gave the title compound as acolourless solid 3.69 g (56%, m.p. 82-83° C.).

d. Silver(3S,4R)-3-chloro-1-(methoxycarbonylmethyl)-2-oxoazetidine-4-thiolate

A solution of methyl[(3S,4R)-4-acetylthio-3-chloro-2-oxo-azetidin-1-yl]acetate (3.64 g,0.0145 mol) in methanol (125 ml) was added with stirring in subduedlight to a solution of silver nitrate (3.2 g, 0.0188 mol) in methanol(55 ml). Triethylamine (2.6 ml, 0.0187 mol) was then added with icecooling, and the reaction was stirred for 1 hr at 5-10° C. followed by40 minutes at room temperature. The mixture was filtered and the solidwashed with methanol (x2) and hexane to yield the title compound, 4.19 g(92%).

e. Methyl [(3S,4R)-4-benzylthio-3-chloro-2-oxoxazetidin-1-yl)acetate

A solution of silver(3S,4R)-3-chloro-1-(methoxycarbonylmethyl)-2-oxoazetidine-4-thiolate(4.12 g, 0.013 mol) in acetonitrile (125 ml) was treated with benzylbromide (2.3 ml, 0.0193 mol) under nitrogen and the mixture was stirredin the dark for 18 hr. The mixture was filtered and the filtrate wasevaporated. Purification by flash chromatography (silica, pet.ether-ethyl acetate) gave the title compound as a colourless solid, 2.93g (75%, m.p. 77-79° C.).

¹ H nmr (CDCl₃) 3.57, 4.0 (each 1H, d, J=18 Hz, NCH₂), 3.72 (3H, s,CH₃), 3.82 (2H, s, SCH₂), 4.62 (1H, d, J=1.7 Hz, H₄), 4.87 (1H, d, J=1.7Hz, H₃), 7.3 (5H, m, Ph-H)

We claim:
 1. A compound of formula (I): ##STR8## in which: R¹ and R²,which may be the same or different, is each selected from hydrogen,halogen or C.sub.(1-8) alkyl;R³ is aryl or arylC.sub.(1-4) alkyl whichsaid aryls may be optionally substituted by up to five substituentsselected from halogen, cyano, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₁₋₆)alkoxy, halo(C₁₋₆)alkyl, hydroxy, amino, mono- ordi(C₁₋₆)alkylamino, acylamino, nitro, carboxy, (C₁₋₆)alkoxycarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₁₋₆)alkoxycarbonyl(C₁₋₆)alkyl,(C₂₋₆)alkenoxycarbonyl(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonyloxy,carboxy(C₁₋₆)alkoxy, (C₁₋₆)alkoxycarbonyl(C₁₋₆)alkoxy,(C₂₋₆)alkenoxycarbonyl(C₁₋₆)alkoxy, (C₁₋₆)alkylcarbonyloxy,(C₁₋₆)alkylthio, (C₁₋₆)alkylsulphinyl, (C₁₋₆)alkylsulphonyl, sulphamoyl,mono- and di-(C₁₋₆)-alkylsulphamoyl, carbamoyl, mono- anddi-(C₁₋₆)alkylcarbamoyl; X is a direct bond and n is 1 or 2; or X is agroup X'(CH₂)_(m) in which X' is CO, CONR⁵, COO, CONR⁵ CO, or CON(H)O inwhich R⁵ is hydrogen or C.sub.(1-6) alkyl and m is 0 or an integer from1 to 12; or a C.sub.(1-12) alkylene chain optionally interupted by X'and n is 0, 1 or 2; and Y is an aryl group optionally substituted by upto five substituents selected from halogen, cyano, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₁₋₆)alkoxy, halo(C₁₋₆)alkyl, hydroxy, amino, mono-or di-(C₁₋₆)alkylamino, acylamino, nitro, carboxy, (C₁₋₆)alkoxycarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₁₋₆)alkoxycarbonyl(C₁₋₆)alkyl,(C₂₋₆)alkenoxycarbonyl(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonyloxy,carboxy(C₁₋₆)alkoxy, (C₁₋₆)alkoxycarbonyl(C₁₋₆)alkoxy,(C₂₋₆)alkenoxycarbonyl(C₁₋₆)alkoxy, (C₁₋₆)alkylcarbonyloxy,(C₁₋₆)alkylthio, (C₁₋₆)alkylsulphinyl, (C₁₋₆)alkylsulphonyl, sulphamoyl,mono- and di-(C₁₋₆)-alkylsulphamoyl, carbamoyl, mono- anddi-(C₁₋₆)alkylcarbamoyl;proved that when R³ and Y are both unsubstitutedphenyl and n is 0 or 1, X is not a direct bond.
 2. A compound as claimedin claim 1 in which R¹ and R² is each hydrogen.
 3. A compound as claimedin claim 1 in which R³ is arylC.sub.(1-3) alkyl.
 4. A compound asclaimed in claim 1 in which, in R³, the aryl group is optionallysubstituted phenyl.
 5. A compound as claimed in claim 1 in which R³ isoptionally substituted benzyl.
 6. A compound as claimed in claim 1 inwhich R³ is 4-carboxybenzyl or a corresponding C.sub.(1-6) alkyl orC.sub.(2-6) alkenyl ester thereof.
 7. A compound as claimed in claim 1in which n is
 1. 8. A compound as claimed in claim 1 in which S(O)_(n)R³ is 4-carboxybenzylsulphinyl or a corresponding C.sub.(1-6) alkyl orC.sub.(2-6) alkenyl ester thereof.
 9. A compound as claimed in claim 1in which X is CO(CH₂)_(m), CONH(CH₂)_(m), COO(CH₂)_(m), CONHCO(CH₂)_(m),CONHO(CH₂)_(m) and C.sub.(1-12) alkylene.
 10. A compound as claimed inclaim 9 in which X is CONH(CH₂)₆.
 11. A compound as claimed in claim 1in which Y is a benzene ring, optionally substituted by up to threefurther substituents.
 12. A compound as claimed in claim 11 in which Yis phenyl optionally substituted by halo.
 13. A compound as claimed inclaim 12 in which Y is 4-chloro or 4-fluoro-phenyl.
 14. A compound offormula (I) as defined in claim 1 in which the relative configurationsat C-4 and the S(O)n moiety, when n=1, are R,S and S,R.
 15. A compoundas claimed in claim 1 in which the absolute configurations at C-4 andthe S(O)n moiety, when n=1, are R and S respectively.
 16. A compound offormula (I) as defined in claim 1 selectedfrom:4-(Benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one; (4R,SR/4S,SS)4-(Benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one; (4R,SS/4S,SR)4-(Benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(Benzylsulphonyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(Benzylthio)-1-(2-phenyl-2-oxoethyl)azetidin-2-one; (4R,SR/4S,SS)4-(Benzylsulphinyl)-1-(2-phenyl-2-oxoethyl)azetidin-2-one; (4R,SS/4S,SR)4-(Benzylsulphinyl)-1-(2-phenyl-2-oxoethyl)azetidin-2-one;4-(Benzylthio)-1-(9-phenyl-2-oxononyl)azetidin-2-one; (4R,SR/4S,SS)4-(Benzylsulphinyl)-1-(9-phenyl-2-oxononyl)azetidin-2-one; (4R,SS/4S,SR)4-(Benzylsulphinyl)-1-(9-phenyl-2-oxononyl)azetidin-2-one;4-(2-Methoxybenzylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR/4S,SS)4-(2-Methoxybenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)4-(2-Methoxybenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(4-Fluorobenzylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR/4S,SS)4-(4-Fluorobenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)4-(4-Fluorobenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(4-methoxybenzylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR/4S,SS)4-(4-methoxybenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)4-(4-methoxybenzylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(phenethylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one; (4R,SR/4S,SS)4-(phenethylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)4-(phenethylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(3-Phenylpropylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR/4S,SS)4-(3-Phenylpropylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)4-(3-Phenylpropylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one; trans3-Methyl-4-(benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR/4S,SS) trans3-Methyl-4-(benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR) trans3-methyl-4-(benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one;N-(6-phenylhexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)N-(6-phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-(6-phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-benzyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide; (4R,SR/4S,SS)N-benzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide; (4R,SS/4S,SR)N-benzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-(4-Phenylbutyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)N-(4-Phenylbutyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-(4-Phenylbutyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-(9-Phenylnonyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)N-(9-Phenylnonyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-(9-Phenylnonyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-Methyl-N-(6-phenylhexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)N-Methyl-N-(6-phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-Methyl-N-(6-phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-[6-(3,5-di-tert-butyl-4-hydroxyphenyl)hexyl]-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-[6-(3,5-Di-tert-butyl-4-hydroxyphenyl)hexyl]-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-6-(4-methoxyphenyl)hexyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)N-6-(4-methoxyphenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-6-(4-methoxyphenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-(6-(4-chlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)-acetamide;(4R,SR/4S,SS)N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-(6-(3-chlorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)-acetamide;(4R,SR/4S,SS)N-(6-(3-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-(6-(3-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-6-(4-hydroxyphenyl)hexyl-(4-benzylthio-2-oxoazetidin-1-yl)-acetamide;(4R,SR/4S,SS)N-6-(4-hydroxyphenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-6-(4-hydroxyphenyl)hexyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-(6-Phenylhexyl)-(4-(4-ethoxycarbonyl)benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)N-(6-Phenylhexyl)-(4-(4-ethoxycarbonyl)benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-(6-phenylhex-1-yl)-4-(4-chlorobenzylthio)-2-oxoazetidin-1-ylacetamide;(4R,SR/4S,SS)N-(6-phenylhex-1-yl)-4-(4-chlorobenzylsulphinyl)-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,SR)N-(6-phenylhex-1-yl)-4-(4-chlorobenzylsulphinyl)-2-oxoazetidin-1-ylacetamide;transN-(6-Phenylhexyl)-(4-benzylthio-3-methyl-2-oxoazetidin-1-yl)acetamide;transN-(6-Phenylhexyl)-(4-benzylsulphinyl-3-methyl-2-oxoazetidin-1-yl)acetamide;N-(6-phenylhexyl)-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide;N-(6-(3,5-dichlorophenyl)hexyl)-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide;N-(6-(3-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;4-(Benzylthio)-1-(3-phenylpropyl)azetidin-2-one; (4R,SR/4S,SS)4-Benzylsulphinyl-1-(3-phenylpropyl)azetidin-2-one; (4R,SS/4S,SR)4-Benzylsulphinyl-1-(3-phenylpropyl)azetidin-2-one;4-Benzylthio-1-(2-phenethyl)azetidin-2-one; (4R,SR/4S,SS)4-Benzylsulphinyl-1-(2-phenethyl)azetidin-2-one; (4R,SS/4S,SR)4-Benzylsulphinyl-1-(2-phenethyl)azetidin-2-one4-(Benzylthio)-1-(4-phenylbutyl)azetidin-2-one; (4R,SS/4S,SR)4-Benzylsulphinyl-1-(4-phenylbutyl)azetidin-2-one; p-Methoxybenzyl [(3S,4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]acetate;(3S,4R)-N-(6-phenylhexyl)-1-(4-benzylthio-3-bromo-2-oxoazetidin-1-yl)acetamide;(3S,4R,SR)-N-(6-phenylhexyl)-4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-ylacetamide;(3S,4R,SS)-N-(6-phenylhexyl)-4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-ylacetamide;(4R,SS/4R,SR)-N-(6-phenylhexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide;(3S,4R)-N-(6-phenylhexyl)-1-(4-benzylthio-3-bromo-2-oxoazetidin-1-yl)acetamide;(4R,SS)-N-(6-(4-chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-[6-(4-Fluorophenyl)hexyl]-4-(4-methoxybenzylthio)-2-oxoazetidin-1-ylacetamide;N-(6-(2,4-Difluorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxybenzylthio)-2-oxoazetidin-1-ylacetamide;N-(6-(3,4-Difluorophenyl)hexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;N-(7-phenylhept-1yl)-4-benzylthio-2-oxoazetidin-1-yl acetamide;N-(6-[4-chlorophenyl]hex-1-yl)-(4-methoxycarbonylbenzylthio)-2-oxoazetidin-1-ylacetamide; N-(5-phenylpentyl)-4-benzylthio-2-oxo-azetidinyl-1-ylacetamide;N-(6-(4-Bromophenyl)hexyl)-4-benzylthio-2-oxoazetidin-1-ylacetamide;N-(6-(4-Fluorophenyl)hexyl)-4-benzylthio-2-oxoazetidin-1-ylacetamide;N-[5-(4-chlorophenyl)pentyl]-4-benzylthio-2-oxo-azetidin-1-yl acetamide;N-[6-(2-Chlorophenyl)hexyl]-4-benzylthio-2-oxo-azetidin-1yl acetamide;N-(6-[4-chlorophenyl]hex-1-yl)-(4-allyloxycarbonylbenzylthio)-2-oxoazetidin-1-yl-acetamide;N-[6-(4-methylphenyl)-hexyl]-[4-benzylsulphinyl-2-oxo-azetidin-1-yl]-acetamide;6-Phenylhexyl (4-benzylthio-2-oxo-azetidin-1-yl)acetate;6-(4-Chlorophenyl)hexyl-[4-benzylthio-2-oxo-azetidin-1yl] acetate;1-(9-Phenylnonyl)-4-benzylthio-2-oxoazetidine;(4R,SR/4S,SS)-N-[6-(4-Fluorophenyl)hexyl]-4-(4-methoxybenzylsulphinyl)-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,SR)-N-[6-(4-Fluorophenyl)hexyl]-4-(4-methoxybenzylsulphinyl)-2-oxoazetidin-1-ylacetamide;(4R,SR/4S,SS)-N-(6-(2,4-Difluorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-(6-(2,4-Difluorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)-N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxybenzylsulphinyl)-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,SR)-N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxybenzylsulphinyl)-2-oxoazetidin-1-ylacetamide;(4R,SR/4S,SS)-N-(6-(3,4-Difluorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-(6-{3,4-Difluorophenyl}hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)-N-(7-phenylhept-1-yl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide;(4R,SR/4S,SR)-N-(7-phenylhept-1-yl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide;(4R,SR/4S,SS)-N-(6-[4-chlorophenyl]hex-1-yl)-(4-methoxycarbonylbenzylsulphinyl)-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,SR)-N-(6-[4-chlorophenyl]hex-1-yl)-(4-methoxycarbonylbenzylsulphinyl)-2-oxoazetidin-1-yl acetamide;(4R,SR/4S,SS)-N-(6-phenylhex-1-yl)-(4-ethoxycarbonylbenzylsulphinyl)-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,SR)-N-(6-[4-chlorophenyl]hex-1-yl)-(4-allyloxycarbonyl-benzylsulphinyl)-2-oxoazetidin-1-ylacetamide; N-(5-phenylpentyl)-4-benzylsulphinyl-2-oxo-azetidinyl-1-ylacetamide;(4R,SR/4S,SS)-N-(5-(4-Chlorophenyl)pentyl)-4-benzylsulphinyl-2-oxo-azetidin-1ylacetamide;(4R,SS/4S,SR)-N-(5-(4-Chlorophenyl)pentyl)-4-benzylsulphinyl-2-oxo-azetidin-1ylacetamide;(4R,SR/4S,SS)-N-[5-(2-Chlorophenyl)hexyl]-4-benzylsulphinyl-2-oxo-azetin-1ylacetamide;N-[5-(2-Chlorophenyl)hexyl]-4-benzylsulphinyl-2-oxo-azetidin-1ylacetamide;(4R,SR/4S,SS)-N-(6-(4-Bromophenyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,SR)-N-(6-(4-Bromophenyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide;(4R,SR/4S,SS)-N-(6-(4-Fluorophenyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,SR)-N-(6-(4-Fluorophenyl)hexyl)-4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide;(4R,SR/4S,SS)-6-Phenylhexyl(4-benzylsulphinyl-2-oxo-azetidin-1-yl)acetate;(4R,SS/4S,SR)-6-Phenylhexyl(4-benzylsulphinyl-2-oxo-azetidin-1-yl)acetate;6-(4-Chlorophenyl)hexyl-(4-benzylsulphinyl-2-oxo-azetidin-1-yl) acetate;(4R,SR/4S,SS)-1-(9-Phenylnonyl)-4-benzylsulphinyl-2-oxoazetidine;(4R,SS/4S,SR)-1-(9-Phenylnonyl)-4-benzylsulphinyl-2-oxoazetidine;N-[6-(4-Methylphenyl)-hexyl]-[4-benzylsulphinyl-2-oxo-azetidin-1-yl]-acetamide;N-[6-(4-Methylphenyl)-hexyl]-[4-benzylsulphinyl-2-oxo-azetidin-1-yl]-acetamide;N-(6-(4-chlorophenyl)hex-1-yl)-((4-carboxybenzylsulphinyl)-2-oxoazetidin-1-yl)acetamide;N-[6-(4-Fluorophenyl)hexyl]-4-(4-methoxybenzylsulphonyl)-2-oxoazetidin-1-ylacetamide;N-(6-(2,4-Difluorophenyl)hexyl)-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide;N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxybenzylsulphonyl)-2-oxoazetidin-1-ylacetamide;N-(6-(3,4-Difluorophenyl)hexyl)-(4-benzylsulphonyl-2-oxoazetidin-1yl)acetamide;N-(7-phenylhept-1-yl)-4-benzylsulphonyl-2-oxoazetidin-1-yl acetamide;N-[6-(4-Chlorophenyl)hexyl]-(4-(4-carboxybenzylsulphonyl)-2-oxo-azetidin-1yl)acetamide;N-[5-(4-Chlorophenyl)pentyl]-4-benzylsulphonyl-2-oxo-azetidin-1ylacetamide;N-[5-(2-Chlorophenyl)hexyl]-4-benzylsulphonyl-2-oxo-azetidin-1ylacetamide;N-(6-(4-Fluorophenyl)hexyl)-4-benzylsulphonyl-2-oxoazetidin-1-ylacetamide;6-Phenylhexyl-[4-benzylsulphonyl-2-oxo-azetidin-1yl] acetate;6-(4-Chlorophenyl)hexyl-(4-benzylsulphonyl-2-oxo-azetidin-1-yl] acetate;1-(9-Phenylnonyl)-4-benzylsulphonyl-2-oxoazetidine;N-[6-(4-Methylphenyl)-hexyl]-[4-benzylsulphonyl-2-oxo-azetidin-1-yl]-acetamide;N-(6-Phenylhexanoyl)-(4-benzylthio-2-oxoazetidin-yl)acetamide;N-(6-Phenylhexanoyl)-(4-benzylsulphinyl-2-oxoazetidin-yl)acetamide;N-(5-Phenylpentyloxy)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)-N-(5-Phenylpentyloxy)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acatamide;(4R,SS/4S,SR)-N-(5-Phenylpentyloxy)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acatamide;4R-N-(6-(4-Chlorophenyl)hexyl)-(4-benzythio-2-oxoazetidin-1-yl)acetamide;4S-N-(6-{4-Chlorophenyl}hexyl)-(4-benzythio-2-oxoazetidin-1-yl)acetamide;(4R,SR)-N-(6-(4-Chlorophenyl)hexyl)-(4-benzysulphinyl-2-oxoazetidin-1-yl)acetamide;(4S,SS)-N-(6-(4-Chlorophenyl)hexyl)-(4-benzysulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS)-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS)-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS)-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS)-N-(6-(4-Chlorophenyl)hexyl)-(4-benzylsulphinyl-2-oxoazetidin-1yl)acetamide;(4S,SR)-N-(6-(4-Chlorophenyl)hexyl)-(4-benzysulphinyl-2-oxoazetidin-1-yl)acetamide;4R-N-(6-(4-Chlorophenyl)hexyl)-(4-benzysulphonyl-2-oxoazetidin-1-yl)acetamide;4S-N-(6-(4-Chlorophenyl)hexyl)-(4-benzysulphonyl-2-oxoazetidin-1-yl)acetamide;4R-(6-Phenylhexyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR)-N-(6-Phenylhexyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-(6-{4-Fluorophenyl}hexyl)-4-(4-allyloxycarbonylbenzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)-N-(6-{4-Fluorophenyl}hexyl)-4-(4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-(6-{4-Fluorophenyl}hexyl)-4-(4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl);(4R,SS/4S,SR)-N-(6-{4-Fluorophenyl}hexyl)-4-(4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-(6-{4-Fluorophenyl}hexyl)-4-(4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-(6-{4-Fluorophenyl}hexyl)-4-(4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-[6-(4-Fluorophenyl)hexyl]-[4-(4-ethyloxycarbonylbenzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide;N-(6-[4-Fluorophenyl]hex-1-yl)-4-carboxybenzylthio)-2-oxoazetidin-1-ylacetamide;N-(6-[4-Fluorophenyl]hex-1-yl)-(4-methylcarboxybenzylthio)-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,R)-N-[6-(4-Fluorophenyl)hexyl]-[4-(4-methyloxycarbonylbenzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide;(4R,SS/4S,SR)-N-(6-{4-Chlorophenyl}hexyl)-4-(4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-(6-{4-Chlorophenyl}hexyl)-4-(4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-(6-{4-Chlorophenyl}hexyl)-4-(4-ethyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(allyloxycarbonylmethyl)benzyl)thio-2-oxo-azetidin-1-yl]-acetamide;N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(allyloxycarbonylmethyl)benzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide;N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(allyloxycarbonylmethyl)benzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide;N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(carboxymethyl)benzyl)thio-2-oxo-azetidin-1-yl]-acetamide;N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(carboxymethyl)benzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide;N-[6-(4-Fluorophenyl)hexyl]-[4-(4-(carboxymethyl)benzyl)sulphinyl-2-oxo-azetidin-1-yl]-acetamide;N-2,4-Dichlorobenzyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)-N-2,4-Dichlorobenzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-2,4-Dichlorobenzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-2,4-Dichlorobenzyl-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide;N-3,4-Dichlorobenzyl-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)-N-3,4-Dichlorobenzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-3,4-Dichlorobenzyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;N-3,4-Dichlorobenzyl-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide;(3S,4R)-N-(6-{4-Fluorophenyl}hexyl)-(3-chloro-4-benzylthio-2-oxoazetidin-1-yl)acetamide;(3S,4R,SR)-N-(6-{4-Fluorophenyl}hexyl)-(3-chloro-4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(SS,3S,4R)-N-(6-{4-Fluorophenyl}hexyl)-(3-chloro-4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide;(3S,4R)-N-(6-(4-Fluorophenyl)hexyl)-4-benzylthio-3-((R)-hydroxyethyl)-2-oxoazetidin-1-ylacetamide;(3S,4R)-N-(6-(4-Fluorophenyl)hexyl)-4-benzylsulphinyl-3-((R)-hydroxyethyl)-2-oxoazetidin-1-ylacetamide;N-(6-phenylhexyl)-(4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)N-(6-phenylhexyl)-(4-(4-methoxyphenyl)sulfinyl)-2-oxoazetidin-1-yl)acetamide;(4R,SS/4S,SR)-N-(6-phenylhexyl)-(4-(4-methoxyphenyl)sulfinyl)-2-oxoazetidin-1-yl)acetamide;N-(6-phenylhexyl)-(4-(4-methoxyphenyl)sulfonyl)-2-oxoazetidin-1-yl)acetamide;N-(6-phenylhexyl)-(4-(3,4-dimethoxyphenylthio)-2-oxoazetidin-1-yl)acetamide(4R,SS/4S,SR)-N-(6-phenylhexyl)-(4-(3,4-dimethoxyphenylsulfinyl)-2-oxoazetidin-1-yl)acetamide;(4R,SR/4S,SS)N-(6-phenylhexyl)-(4-(3,4-dimethoxyphenylsulfinyl)-2-oxoazetidin-1-yl)acetamide;N-(6-phenylhexyl)-(4-(4-chlorophenylthio)-2-oxoazetidin-1-yl)acetamide;4-(Phenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4S)-4-(Phenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R)-4-(Phenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(2-Methoxyphenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(3,4-dimethoxyphenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(3-methoxyphenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(4-methoxyphenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR/4S,SS) 4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)-4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR)-4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS)-4-(Phenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR/4S,SS)4-(2-Methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)-4-(2-Methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)-4-(3,4-dimethoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR/4S,SS)4-(3-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)-4-(3-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SR/4S,SS)4-(4-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;(4R,SS/4S,SR)-4-(4-methoxyphenylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(Phenylsulphonyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;4-(2-Methoxyphenylsulphonyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one;N-[6-(4-Chlorophenyl)hexyl]-4-(4-methylphenylthio)-2-oxoazetidin-1-ylacetamide;(4R,SR/4S,SS)-N-[6-(4-chlorophenyl)hexyl]-4-(4-methylphenyl)sulfinyl-2-oxo-azetidinyl-1-ylacetamide;(4R,SS/4S,SR)-N-[6-(4-chlorophenyl)hexyl]-4-(4-methylphenyl)sulfinyl-2-oxo-azetidinyl-1-ylacetamide;N-[6-(4-chlorophenyl)hexyl]-4-(4-methylphenyl)sulfonyl-2-oxo-azetidinyl-1-ylacetamide;(+/-)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylthio-2-oxoazetidin-1-ylacetamidehydrate;(-)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylthio-2-oxoazetidin-1-ylacetamidehydrate;(+)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylthio-2-oxoazetidin-1-ylacetamidehydrate;(4R,SR/4S,SS)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,SR)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide;(-)-(4R,SR or4S,SS)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide;(+)-(4R,SS or4S,SR)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide;(+)-(4R,SS or4S,SR)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide;(-)-(4R,SR or4S,SS)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide;N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide;(-)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide;(+)-N-[6-(4-Chlorophenyl)hexyl]-4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide;N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxyphenylthio)-2-oxoazetidin-1-ylacetamide;(4R,SR/4S,SS)-N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxyphenylsulfinyl)-2-oxoazetidin-1-ylacetamide;(4R,SS/4S,SR)-N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxyphenylsulfinyl)-2-oxoazetidin-1-ylacetamide;N-[6-(4-Chlorophenyl)hexyl]-4-(4-methoxyphenylsulfonyl)-2-oxoazetidin-1-ylacetamideN-Benzyl-[4-(4-methoxyphenylthio)-2-oxoazetidin-1-yl]acetamide;(4R,SR/4S,SS)-N-Benzyl-[4-(4-methoxyphenylsulphinyl)-2-oxoazetidin-1-yl]acetamide;and(4R,SS/4S,SR)-N-Benzyl-[4-(4-methoxyphenylsulphinyl)-2-oxoazetidin-1-yl]acetamide;inwhich 3R or 3S describes the absolute configuration at the C3 chiralcentre in the azetidinone, 4R or 4S describes the absolute configurationat the C4 chiral centre in the azetidinone, and SR or SS describes theabsolute configuration at sulfoxide chiral centre, the "S" refers tosulphur; and "/" denotes "and" and rather than "or".
 17. Apharmaceutical composition comprising a compound of formula (I) asdefined in claim 1 and a pharmaceutically acceptable carrier.
 18. Amethod of treating atheroscelorsis that comprises administering ananti-atherosclerotic effective amount of a compound of formula (I) asdefined in claim 1 to a patient in need thereof.
 19. A compound offormula (VII) ##STR9## in which: Y is (C₁₋₆)alkyl; andn, R¹, R² and R³are as defined in claim
 1. 20. A compound of formula (VII) as defined inclaim 19 selected from:Methyl-(4-benzylthio-2-oxoazetidin-1-yl)acetate;Methyl (4-(4-methoxybenzylthio)-2-oxoazetidin-1-yl)acetate; Methyl(4-methoxyphenylthio-2-oxoazetidin-1-yl)acetate; and Methyl(4-phenylthio-2-oxoazetidin-1-yl)acetate.
 21. A process for preparing acompound of formula (I) as defined in claim 1 which processcomprises:(i) treating an azetidinone of formula (II): ##STR10## inwhich: n, R¹, R² and R³ are as hereinbefore defined;with an alkylatingagent of the formula (III):

    ZCH.sub.2 XY                                               (III)

in which Z is a leaving group; and X and Y are as hereinbefore defined;under alkylating conditions; (ii) when X denotes a group CONR⁵ (CH₂)_(m)or CONHO(CH₂)_(m), treating an acid of the formula (IV): ##STR11## inwhich: n, R¹, R² and R³ are as hereinbefore defined;with an amine of theformula (V):

    NHR.sub.5 (CH.sub.2).sub.m Y                               (V)

or a hydroxylamine of the formula (VI):

    NH.sub.2 O(CH).sub.2).sub.m Y                              (VI)

in which Y and m are as hereinbefore defined, under amide or hydroxamatebond forming conditions; (III) when X denotes a group COO(CH₂)_(m),treating a compound of formula (IV) as hereinbefore defined with analcohol Y(CH₂)_(m) OH or an activated derivative thereof under esterforming conditions; or (iv) treating a compound of formula (VIII):##STR12## in which R¹, R², R³, X and Y are as hereinbefore defined; withan alkylating agent of the formula (IX):

    R.sup.3 Z                                                  (IX)

in which R³ and Z are as hereinbefore defined; under alkylatingconditions.